1. Field of the Invention
The present invention relates to substituted imidazolidine derivatives of the formula I 
in which B, E, W, Y, R, R2, R3, R30, e and h have the meanings indicated below. The compounds of the formula I are valuable pharmaceutical active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leucocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy or prophylaxis of illnesses which are caused by an undesired extent of leucocyte adhesion and/or leucocyte migration or are associated therewith, or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use, in particular as pharmaceutical active compounds, and pharmaceutical preparations which contain compounds of the formula I.
2. Description of Related Art
The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extracellular matrix-binding processes. They have an xcex1xcex2-heterodimeric structure and exhibit a wide cellular distribution and a high extent of evolutive conservation. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the xcex22 subfamily with the representatives LFA-1. Mac-1 and p 150/95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies xcex21 and xcex23, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the xcex21 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (xcex14xcex21) is atypical, insofar as it is mainly restricted to lymphoid and myeloid cells and is responsible in these for cell-cell interactions with a large number of other cells. For example, VLA-4 mediates the interaction of T and B lymphocytes with the heparin II-binding fragment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin II-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347).
The leucocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin). which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leucocyte function-associated antigen 1) on leucocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leucocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first known as INCAM-110) was identified as an adhesion molecule that is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 does not take place here due to an interaction of the VLA-4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). VLA-4, however, also occurs on other leucocytes, and the adhesion of leucocytes other than lymphocytes is also mediated via the VCAM-1/VLA-4 adhesion mechanism. VLA-4 thus represents an individual example of a xcex21 integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell-cell interactions and in cell-extracellular matrix interactions.
The cytokine-induced adhesion molecules play an important part in the recruitment of leucocytes into extravascular tissue regions. Leucocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leucocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leucocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which carry the integrin VLA-4 (xcex14xcex21), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it and the VCAM-1/VLA-4 mechanism have the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp. Med. 1996, 183, 2175).
The VCAM-1/VLA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from cytokine-induced endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman""s capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also found to be expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1/VLA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989, 246, 1303).
The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino acid sequences to the domains 1, 2 and 3. In a further form consisting of six domains, designated here as VCAM-6D, the fourth domain is removed by alternative splicing. VCAM-6D can also bind VLA-4 expressing cells.
Further details on VLA-4. VCAM-1, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 1995, 16, 379.
On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesion processes, which are of importance, for example, in infections, inflammations or atherosclerosis, it has been attempted to intervene into these adhesion processes to control illnesses, in particular, for example, inflammations (Osborn et al., Cell 1989, 59, 1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mABs)of this type, which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mABs HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and to VCAM-1-transfected COS cells. The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells, Jurkat cells CT-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs which cause VCAM-6D and VCAM-7D to be expressed. In vitro data with antibodies which are directed against the xcex14 subunit of VLA-4 show that the adhesion of lymphocytes to synovial endothelial cells is blocked, an adhesion which plays a part in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207).
In vivo experiments have shown that an experimental autoimmune encephalomyelitis can be inhibited by anti-xcex14 mAB. The migration of leucocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the xcex14 chain of VLA-4. The influencing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leucocytes into inflamed lung tissue (WO-A-93/13798). The administration of anti-VLA-4 antibodies inhibited the late-phase reaction and airway overreaction in allergic sheep.
The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in man, the administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation.
Moreover, it was possible to show that VLA-4-dependent cell adhesion plays a part in the following clinical conditions including the following chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Elices et al., J. Clin. Invest. 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Elices et al., Clin. Exp. Rheumatol. 1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria (Ockenhouse et al., J. Exp. Med. 1992, 176, 1183), arteriosclerosis (O""Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et al., Transplantation Proceedings 1994, 26, 867-868), various malignancies, for example melanoma (Renkonen et al., Am. J. Pathol. 1992, 140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) and others (Albelda et al., J. Cell Biol. 1991, 114, 1059).
VLA-4 blocking by suitable antagonists accordingly offers effective therapeutic possibilities, in particular, for example, of treating various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis in this case results, as already stated, from the fact that leucocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium, and that the VLA-4 receptor plays a part in this adhesion. The fact that VCAM-1 is induced by inflammatory agents on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of various leucocytes into areas of infection and inflammatory foci has already been discussed above. At the same time, T cells adhere to activated endothelium mainly via the LFA-1/ICAM-1 and VLA-4/VCAM-1 adhesion mechanisms (Springer, Cell 1994, 76, 301). On most synovial T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovial T cells to fibronectin has been observed (Laffon et al., J. Clin. Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992, 149, 1424). VLA-4 is upregulated both in the course of its expression and with respect to its function on T lymphocytes of the rheumatoid synovial membrane. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been observed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an important therapeutic target molecule.
The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in the Patent Applications WO-A-93/13798, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790. In the Patent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216, peptide compounds are described as VLA-4 antagonists. The use of antibodies and peptide compounds as pharmaceuticals, however, has some disadvantages, for example lack of oral availability, easy degradability or immunogenic action on longer-term use, and there is thus a need for VLA-4 antagonists having a favorable profile of properties for use in therapy and prophylaxis.
WO-A-95/14008, WO-A-94/21607 (U.S. Pat. No. 5,658,935), WO-A-93/18057, EP-A-449 079 (U.S. Pat. No. 5.686,421), EP-A-530 505 (U.S. Pat. No. 5,389,614), EP-A-566 919 (U.S. Pat. No. 5,397,796), EP-A-580 008 (U.S. Pat. No. 5,424,293)and EP-A-584 694 (U.S. Pat. No. 5,554,594) describe substituted 5-membered ring heterocycles which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting actions. EP-A-796 855 describes further heterocycles which are inhibitors of bone resorption. EP-A-842 943, EP-A842 945 and EP-A842 944 (German Patent Applications 19647380.2, 19647381.0 and 19647382.9) describe that compounds from this series and further compounds surprisingly also inhibit leucocyte adhesion and are VLA-4 antagonists. Further investigations showed that the compounds of the present application are also strong inhibitors of leucocyte adhesion and/or are VLA-4 antagonists.
The present invention relates to compounds of the formula I 
in which
W is a divalent radical selected from the group consisting of R1xe2x80x94Axe2x80x94C(R13), R1xe2x80x94Axe2x80x94C(R13)xe2x95x90C, 
xe2x80x83in which the ring systems 
xe2x80x83can contain one or two identical or different heteroatoms selected from the group consisting of N, O and S, can be saturated or mono- or polyunsaturated and can be substituted by 1, 2 or 3 identical or different substituents R13 and/or by one or two doubly bonded oxygen atoms and/or sulfur atoms, and in which L is C(R13) or N and in which m1 and m2 independently of one another are one of the numbers 0, 1, 2, 3, 4, 5 and 6, but the sum m1+m2 is one of the numbers 1, 2, 3, 4, 5 or 6;
Y is a carbonyl group, thiocarbonyl group or methylene group;
A is a direct bond, one of the divalent radicals (C1-C6)-alkylene, (C3-C7)-cycloalkylene, phenylene, phenylene-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl or a divalent radical of a 5-membered or 6-membered, saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur, where in the radicals phenylenealkyl and phenylenealkenyl the radical R1 is bonded to the phenylene group;
B is a divalent radical selected from the group consisting of (C1-C6)-alklene, (C2-C6)-alkenylene, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alkylenephenyl and (C1-C3)-alkylenephenyl-(C1-C3)-alkyl, where the (C1-C6)-alkylene radical and the (C2-C6)-alkenylene radical are unsubstituted or substituted by one or more identical or different radicals selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is tetrazolyl, (R8O)2P(O), R10OS(O)2, R9NHS(O)2, R6CO, R7CO, R10CO, HCO, R8Oxe2x80x94CH2, R8COxe2x80x94Oxe2x80x94CH2, R8aOxe2x80x94COxe2x80x94Oxe2x80x94CH2 or (R8O)2P(O)xe2x80x94Oxe2x80x94CH2;
R is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, where all radicals R are independent of one another and the radicals R can be identical or different;
R1 is hydrogen, (C1-C10)-alkyl which can optionally be mono- or polysubstituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, R21-((C6-C14)-aryl) optionally substituted in the aryl radical, (R21xe2x80x94((C6-C14)-aryl))-(C1-C8)-alkyl optionally substituted in the aryl radical, the radical Het-, Het-(C1-C8)-alkyl or one of the radicals Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94R20xe2x80x94, X1xe2x80x94NHxe2x80x94R20xe2x80x94, R21Oxe2x80x94R20xe2x80x94, R21N(R21)xe2x80x94R20xe2x80x94, R21C(O)xe2x80x94, R21Oxe2x80x94C(O)xe2x80x94, R22N(R21)xe2x80x94C(O)xe2x80x94, R22C(O)xe2x80x94N(R21)xe2x80x94, R21Oxe2x80x94Nxe2x95x90, Oxe2x95x90 and Sxe2x95x90;
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C10)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, optionally substituted (C6-C14)-arylcarbonyl, optionally substituted (C6-C14)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl which can also be substituted in the aryl radical, cyano, hydroxyl, (C1-C6)-alkoxy, (C6-C14)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, or amino;
Xxe2x80x2 has one of the meanings of X or is Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), in which Rxe2x80x2 and Rxe2x80x3 independently of one another have the meanings of X;
R2 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
R3 is hydrogen, (C1-C10)-alkyl which can optionally be mono- or polysubstituted by fluorine, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, CON(CH3)R4, CONHR4, COOR21, COOR15, CON(CH3)R15 or CONHR15;
R4 is hydrogen or (C1-C10)-alkyl which is unsubstituted or is mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C10)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO, tetrazolyl, trifluormethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, or a radical of an optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring which can be aromatic, partially saturated or completely saturated and which can contain one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which can also be substituted in the aryl radical, or the radical of a dipeptide, tripeptide or tetrapeptide, and their esters and amides, in which free functional groups can be protected by protective groups customary in peptide chemistry and in which the nitrogen atoms in the amide bonds in the group R6xe2x80x94CO can carry a radical R as a substituent;
R7 is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, in which additional ring nitrogen atoms can carry identical or different radicals selected from the group consisting of hydrogen, Rh, HCO, RhCO, RhOxe2x80x94CO, HOxe2x80x94COxe2x80x94(C1-C4)-alkyl and RhOxe2x80x94COxe2x80x94(C1-C4)-alkyl as substituents and Rh is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
R8 is hydrogen, (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl which can also be substituted in the aryl radical, where the radicals R8 are independent of one another and can be identical or different;
R8a independently of R8 has one of the meanings of R8 with the exception of hydrogen;
R9 is hydrogen, aminocarbonyl, (C1-C10)-alkylaminocarbonyl, (C3-C8)-cycloalkylaminocarbonyl, optionally substituted (C6-C14)-arylaminocarbonyl, (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8)-cycloalkyl;
R10 is hydroxyl, (C1-C10)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-arylcarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, (C6-C14)-aryl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-aryloxycarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, amino, mono- or di-(C1-C10)-alkyl)-amino or R8R8Nxe2x80x94COxe2x80x94(C1-C6)-alkoxy, in which the radicals R8 are independent of one another and can be identical or different;
R11 is hydrogen, 12a, R12axe2x80x94CO, Hxe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS, R12axe2x80x94S(O)2 or R12bxe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen, (C1-C6)-alkyl which can optionally be mono- or polysubstituted by fluorine, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 24-membered, bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl and oxo;
R20 is a direct bond or a divalent (C1-C6)-alkylene radical;
R21 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, the radical Het- or Het-(C1-C8)-alkyl, in which alkyl radicals can be monosubstituted or polysubstituted by fluorine and the radicals R21, if they occur more than once, are independent of one another and can be identical or different;
R22 is R21xe2x80x94, R21Oxe2x80x94, R21N(R21)xe2x80x94, R21C(O)xe2x80x94, R21Oxe2x80x94C(O)xe2x80x94, R21N(R21)xe2x80x94C(O)xe2x80x94, R21N(R21)xe2x80x94C(xe2x95x90N(R21))xe2x80x94 or R21C(O)xe2x80x94N(R21)xe2x80x94;
R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94COxe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94R31, R32xe2x80x94COxe2x80x94R31, R32xe2x80x94CSxe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94R31 or R12axe2x80x94Oxe2x80x94COxe2x80x94N(R)xe2x80x94R31, where R30 cannot be R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 if at the same time W is R1xe2x80x94Axe2x80x94C(R13), A is a direct bond and R1 and R13 are hydrogen;
R31 is the divalent radical xe2x80x94R33xe2x80x94R34xe2x80x94R35xe2x80x94R36xe2x80x94, where R36 is bonded to the nitrogen atom in the imidazolidine ring in the formula I;
R32 is hydrogen, (C1-C8)-alkyl, which can optionally be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical;
R33 is a direct bond or a divalent (C1-C6)-alkylene radical;
R34 is a divalent radical selected from the group consisting of (C1-C8)-alkylene, (C3-C12)-cycloalkylene, (C6-C12)-bicycloalkylene, (C6-C12)-tricycloalkylene, optionally substituted (C6-C14)-arylene and optionally substituted heteroarylene;
R35 is a direct bond or a divalent (C1-C8)-alkylene radical;
R36 is a direct bond, the group xe2x80x94COxe2x80x94 or the group xe2x80x94S(O)nxe2x80x94;
Het is a radical of a monocyclic or polycyclic, 4-membered to 14-membered, aromatic or nonaromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms from the group consisting of N, O and S as ring members and can optionally be substituted by one or more identical or different substituents;
e and h independently of one another are 0 or 1;
n is 1 or 2, where the numbers n, if they occur more than once, are independent of one another and can be identical or different;
in any their stereoisomeric forms and mixtures thereof in any ratios, and their physiologically tolerable salts.
Further objects, features, and advantages of the invention, will become apparent from the detailed description that follows.
In the compounds of the invention, if radicals or substituents can occur more than once in the compounds of the formula I, they can all independently of one another have the meanings indicated and can in all cases be identical or different. In combined radicals, for example arylalkyl, the free bond, via which the radical is bonded, starts from the component indicated at the right end of the name, i.e. in the case of the arylalkyl radical from the alkyl group which carries an awl group as substituent.
Alkyl radicals can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. Examples of suitable alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. If alkyl radicals are substituted by fluorine atoms, they can contain, for example, 1, 2, 3, 4, 5, 6 or 7 fluorine atoms, if not stated otherwise. For example, in a fluorine-substituted alkyl radical, a methyl group can be present as a trifluoromethyl group.
Alkylene radicals (=alkanediyl radicals), i. e., divalent radicals derived from an alkane, can likewise be straight-chain or branched. They can be bonded via any desired positions. Examples of alkylene radicals include the divalent radicals corresponding to the abovementioned monovalent radicals, for example methylene, ethylene (=1,2-ethylene or 1,1-ethylene), trimethylene (=1,3-propylene), tetramethylene (=1,4-butylene), pentamethylene, hexamethylene or methylene or ethylene substituted by alkyl radicals. Examples of substituted methylene are methylene groups which are substituted by a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group or an n-hexyl group. Substituted ethylene can be substituted either on one carbon atom or on the other carbon atom or also on both carbon atoms.
Alkenyl radicals and alkenylene radicals (=alkenediyl radicals) as well as alkynyl radicals can also be straight-chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, examples of alkenylene radicals are vinylene, propenylene, or butenylene, and examples of alkynyl radicals are ethynyl, 1-propynyl or propargyl.
Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, which, however, can also be substituted, for example, by (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. These explanations for the monovalent cycloalkyl radicals correspondingly apply to cycloalkylene radicals (=cycloalkanediyl radicals), i.e. divalent radicals derived from cycloalkanes. Cycloalkylene radicals can be bonded via any desired positions.
Bicycloalkyl radicals, tricycloalkyl radicals and the 6-membered to 24-membered bicyclic and tricyclic radicals representing R16 can be formally obtained by abstraction of a hydrogen atom from bicycles or tricycles. The parent bicycles and tricycles can contain only carbon atoms as ring members, they can thus be bicycloalkanes or tricycloalkanes, but in the case of the radicals representing R16 they can also contain one to four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur, they can thus be aza-, oxa- and thiabicyclo- and -tricycloalkanes. If heteroatoms are contained, preferably one or two heteroatoms, in particular nitrogen atoms or oxygen atoms, are contained. The heteroatoms can occupy any desired positions in the bicyclic or tricyclic structure; they can be located in the bridges or, in the case of nitrogen atoms, also on the bridgeheads. Both the bicycloalkanes and tricycloalkanes and their heteroanalogs can be completely saturated or can contain one or more double bonds; preferably they contain one or two double bonds or are, in particular, completely saturated. Both the bicycloalkanes and tricycloalkanes as well as the heteroanalogs and both the saturated and the unsaturated representatives can be unsubstituted or can be substituted in any desired suitable positions by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, for example methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be located in any desired position of the molecule, the radical can thus be bonded via a bridgehead atom or an atom in a bridge. The free bond can also be located in any desired stereochemical position, for example in an exo position or an endo position.
Examples of parent structures of bicyclic ring systems, from which a bicyclic radical can be derived, are norbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane, examples of heteroatom-containing, unsaturated or substituted systems are 7-azabicyclo[2.2.1 ]heptane, bicyclo[2.2.2]oct-5-ene and camphor (=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).
Examples of systems from which a tricyclic radical can be derived are twistane (=tricyclo[4.4.0.03,8]decane), adamantane (=tricyclo[3.3.1.13,7]decane), noradamantane (=tricyclo[3.3.1.03,7]nonane), tricyclo[2.2.1.02,6]heptane, tricyclo[5.3.2.04,9]dodecane, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecane.
Preferably, bicyclic or tricyclic radicals are derived from bridged bicycles or tricycles. i.e., from systems in which rings have two or more than two atoms in common. Additionally preferred, if not stated otherwise, are also bicyclic or tricyclic radicals having 6 to 18 ring members, particularly preferably those having 6 to 14 ring members, very particularly preferably those having 7 to 12 ring members.
Specifically particularly preferred bicyclic or tricyclic radicals which can represent, for example, a bicycloalkyl group or a tricycloalkyl group, are the 2-norbornyl radical, both that having the free bond in the exo position and that having the free bond in the endo position, the 2-bicyclo[3.2.1]octyl radical, the adamantyl radical, both the 1-adamantyl radical and the 2-adamantyl radical, the homoadamantyl radical and the noradamantyl radical, for example the 3-noradamantyl radical. Additionally preferred are the 1-adamantyl radical and the 2-adamantyl radical.
The above explanations for the monovalent bicycloalkyl radicals and tricycloalkyl radicals correspondingly apply to the divalent bicycloalkylene radicals and tricycloalkylene radicals (=bicycloalkanediyl radicals and tricycloalkanediyl radicals).
(C6-C14)-Aryl groups include, for example, phenyl, naphthyl for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, (C6-C10)-aryl groups are, for example, 1-naphthyl, 2-naphthyl and phenyl. Biphenylyl radicals, naphthyl radicals and in particular phenyl radicals are preferred aryl radicals. Aryl radicals, in particular phenyl radicals, can be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted, trisubstituted or tetrasubstituted, by identical or different radicals. Substituted aryl radicals, in particular phenyl radicals, are preferably substituted by radicals selected from (C1-C8)-alkyl, in particular (C1-C4)-alkyl such as methyl; (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy such as methoxy; (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, which is substituted by one or more fluorine atoms, for example 1, 2, 3, 4 or 5 fluorine atoms, such as trifluoromethoxy; halogen; nitro; amino; trifluoromethyl; hydroxyl; hydroxy-(C1-C4)-alkyl such as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl; methylenedioxy; ethylenedioxy, formyl; acetyl; cyano; hydroxycarbonyl; aminocarbonyl; (C1-C4)-alkoxycarbonyl; phenyl; phenoxy; benzyl; benzyloxy, tetrazolyl. The same applies, for example to substituted aryl radicals, in groups such as arylalkyl, arylcarbonyl, etc. Arylalkyl radicals are, for example, 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl and in particular benzyl, all of which can also be substituted. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C1-C8)-alkyl radicals, in particular (C1-C4)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl; benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C1-C8)-alkoxy radicals, in particular (C1-C4)-alkoxy radicals, for example 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 2,3,4-trimethoxybenzyl; 3,4-methylenedioxybenzyl; trifluoromethoxybenzyl radicals; nitrobenzyl radicals, for example 2-, 3- and 4-nitrobenzyl; halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl and 2-, 3-, and 4-fluorobenzyl, 3,4-dichlorobenzyl, pentafluoro-benzyl; trifluoromethylbenzyl radicals, for example 3- and 4-trifluoromethylbenzyl or 3,5-bistrifluoromethylbenzyl. Substituted arylalkyl radicals, however, can also contain substituents different from one another. In the compounds of the formula I, however, in general not more than two nitro groups can be present in the molecule.
In monosubstituted phenyl radicals, the substituent can be located in the 2-position, the 3-position or the 4-position. Disubstituted phenyl can be substituted in the 2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the 3,4-position or the 3,5-position. In trisubstituted phenyl radicals, the substituents can be situated, for example, in the 2,3,4-position, the 2,3,5-position, the 2,4,5-position, the 2,4,6-position, the 2,3,6-position, or the 3,4,5-position.
The above explanations for the monovalent aryl radicals apply correspondingly to the divalent arylene radicals, i.e., divalent radicals derived from aromatics. Arylene radicals can be linked via any desired positions. An example of arylene radicals is phenylene radicals, which can be present, for example, as 1,4-phenylene or as 1,3-phenylene.
Phenylene-alkyl is in particular phenylenemethyl (xe2x80x94C6H4xe2x80x94CH2xe2x80x94) or phenyleneethyl (for example (xe2x80x94C6H4xe2x80x94CH2xe2x80x94CH2xe2x80x94), alkylene-phenyl is in particular methylenephenyl (xe2x80x94CH2xe2x80x94C6xe2x80x94H4xe2x80x94). Phenylene-alkenyl is in particular phenyleneethenyl or phenylenepropenyl.
Heteroaryl is a radical of a monocyclic or polycyclic aromatic system having 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, O and S. If several heteroatoms are contained, these can be identical or different. Heteroaryl radicals can also be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, by identical or different radicals selected from the (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, which is substituted by one or more, for example 1, 2, 3, 4 or 5, fluorine atoms, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. Preferably heteroaryl is a monocyclic or bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different heteroatoms selected from N, O and S and which can be substituted by 1, 2, 3 or 4, in particular 1 to 3, identical or different substituents selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Particularly preferably, heteroaryl is a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-membered to 6-membered monocyclic aromatic radical which contains 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms selected from N, O and S and can be substituted by 1 or 2 identical or different substituents selected from the group of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.
Heterocycles which represent monocyclic or bicyclic, 5-membered to 12-membered heterocyclic rings can be aromatic or partially or completely saturated. They can be unsubstituted or substituted on one or more carbon atoms or on one or more nitrogen atoms by identical or different substituents, such as is indicated for the radical heteroaryl.
In particular, the heterocyclic ring can be monosubstituted or polysubstituted, for example, monosubstituted, disubstituted, trisubstituted, or pentasubstituted, on carbon atoms by identical or different radicals selected from (C1-C8)-alkyl, for example (C1-C4)-alkyl, (C1-C8)-alkoxy, for example (C1-C4)-alkoxy such as methoxy, phenyl-(C1-C4)-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl, and/or ring nitrogen atoms in heterocyclic rings and in heteroaryl radicals can be substituted by (C1-C8)-alkyl, for example (C1-C4)-alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyl-(C1-C4)-alkyl, for example benzyl.
The radical Het comprises aromatic heterocycles and thus also the groups representing heteroaryl, insofar as these come under the definition of Het with respect to the number of ring members and heteroatoms. However, Het additionally also comprises nonaromatic heterocycles which are completely saturated or which contain one or more double bonds in the ring system. Het can be substituted on nitrogen atoms and/or carbon atoms by one or more, for example 1, 2, 3 or 4, identical or different substituents, for example by (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, heteroaryl, heteroaryl-(C1-C8)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, optionally substituted phenoxy, benzyloxy, halogen, nitro, amino, (C1-C8)-alkylamino, di-(C1-C8)-alkyl)-amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl and generally by ester groups, acyl groups, oxo, thioxo, where alkyl radicals can be monosubstituted or polysubstituted by fluorine.
Examples of parent structures of heterocycles from which a heteroaryl radical, the radical Het, the radical of a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring, the divalent radical of a 5-membered or 6-membered heterocyclic, the heterocyclic radical representing R7 or a heterocyclic radical representing R16 can be derived, insofar as in the individual case they come under the respective definition, include pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, xcex2-carboline and benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.
Nitrogen heterocycles can also be present as N-oxides or as quaternary salts.
Radicals which can be heteroaryl or the radical of a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring include, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or 2-benzothiazolyl or, as radicals of partially saturated or completely saturated heterocyclic rings, for example also dihydropyridinyl, pyrrolidinyl, for example 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxolanyl.
The explanations for heteroaryl radicals correspondingly apply to the divalent heteroarylene radicals, i.e., the divalent radicals derived from heteroaromatics.
Heterocyclic radicals representing the radical R7 can be unsubstituted or monosubstituted or polysubstituted, for example disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different substituents on the carbon atoms and/or on additional ring nitrogen atoms. Carbon atoms can be substituted, for example, by (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, oxo, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl, in particular by (C1-C4)-alkyl, for example methyl, ethyl or tert-butyl, (C1-C4)-alkoxy, for example methoxy, hydroxyl, oxo, phenyl, phenoxy, benzyl, benzyloxy. Sulfur atoms can be oxidized to the sulfoxide or to the sulfone. Examples of the radical Het include 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-substituted 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-thiomorpholinyl, 1,1-dioxo-4-thiomorpholinyl, perhydroazepin-1-yl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,2,6,6-tetramethyl-1-piperazinyl, 4-acetyl-1-piperazinyl, and 4-ethoxycarbonyl-1-piperazinyl.
Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
The substituent on a substituted alkylene radical or alkenylene radical representing B can on the one hand contain a cycle when it is a substituent selected from the group of (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6) optionally substituted in the heteroayl radical. On the other hand the substituent on a substituted alkylene radical or alkenylene radical representing B can be acyclic if it is a substituent selected from the group of (C1-C8)-alkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl. The acyclic substituents can contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms and, in the case of a saturated alkyl radical, also 1 carbon atom. In the case of the alkenyl radicals and alkynyl radicals, the double bond or triple bond can be located in any desired position and in the case of the double bond can have the cis configuration or trans configuration. As explained above, these alkyl radicals, alkenyl radicals, and alkynyl radicals can be straight-chain or branched.
Examples of substituents which may be mentioned in particular which the (C1-C6)-alkylene radical or (C2-C6)-alkenylene radical representing B can carry are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl, tert-butyl, tert-pentyl, neopentyl, neohexyl, 3-methylpentyl, 2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 6-hexynyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-biphenylylmethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylpropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(3-indolyl)ethyl.
The radical of an amino acid, imino acid or azaamino acid or of a dipeptide, tripeptide or tetrapeptide representing R6 is obtained from the corresponding amino acid, imino acid or azaamino acid or the dipeptide, tripeptide or tetrapeptide as customary in peptide chemistry by formally removing a hydrogen atom from the N-terminal amino group or from the imino group. This group is then linked in peptide fashion through an amide bond to the CO group in the group R6xe2x80x94CO via the free bond on the amino group or the imino group resulting in this way.
The natural and unnatural amino acids can be present in all stereochemical forms, for example in the D form, the L form or in the form of a mixture of stereoisomers, for example in the form of a racemate. Preferred amino acids are xcex1-amino acids and xcex2-amino acids, xcex1-amino acids are particularly preferred. Suitable amino acids which may be mentioned, for example, are (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, xcex3Abu, ABz, 2ABz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(p-chlorophenyl)aminoacetic acid.
If R6 is the radical of a natural or unnatural xcex1-amino acid then this radical can correspond, for example, to the formula xe2x80x94N(R)xe2x80x94CH(SC)xe2x80x94COxe2x80x94AG in which COxe2x80x94AG is the acid group of the amino acid or a derivative thereof, for example an ester group, an amide group or a group containing a peptide radical, and SC is the side chain of the xcex1-amino acid, i.e., for example, one of the substituents which are contained in the xcex1-position of the abovelisted xcex1-amino acids. Examples of side chains are alkyl radicals, for example the methyl group in alanine or the isopropyl group in valine, the benzyl radical in phenylalanine, the phenyl radical in phenylglycine, the 4-aminobutyl radical in lysine or the hydroxycarbonyl methyl group in aspartic acid. Apart from by their chemical structure, such side chains and thus the amino acids can also be arranged in groups on the basis of their physicochemical properties, for example lipophilic side chains can be differentiated from hydrophilic side chains which contain polar groups. Examples of lipophilic side chains which can be contained in amino acids representing R6 are alkyl radicals, arylalkyl radicals or aryl radicals. The same applies to amino acids which are part of a radical of a dipeptide, tripeptide or tetrapeptide representing R6.
Azaamino acids are natural or unnatural amino acids in which a CH unit is replaced by a nitrogen atom. For example, in xcex1-amino acids the central structural unit 
is replaced by 
Suitable radicals of imino acids are, in particular, radicals of heterocycles selected from the following group: pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]decane-3-carboxylic acid; decahydrocyclohepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, all of which can optionally be substituted (see following formulae): 
The heterocycles on which the above radicals are based are disclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EPA 89,637; EP-A 90,341; EP-A 90,362; EPA 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682. All of these documents are incorporated by reference in their entirety,
Dipeptides, tripeptides and tetrapeptides can contain natural or unnatural amino acids, imino acids and azaamino acids as structural units. In addition, the natural or unnatural amino acids, imino acids, azaamino acids, dipeptides, tripeptides and tetrapeptides can also be present in the form of derivatives of the carboxylic acid group, for example as esters or amides, such as, for example, as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, isobutyl ester, tertbutyl ester, benzyl ester, unsubstituted amide, methylamide, ethylamide, semicarbazide or xcfx89-amino-(C2-C8)-alkylamide.
Functional groups in radicals of amino acids, imino acids, azaamino acids, dipeptides, tripeptides and tetrapeptides as well as in other parts of the compounds of the formula I can be present in protected form. Suitable protective groups such as, for example, urethane protective groups, carboxyl protective groups and side chain protective groups are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23, and in Bxc3xcllesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35, both incorporated herein by reference in their entirety. The following may be mentioned in particular. Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerable salts of the compounds of the formula I are, in particular, pharmaceutically utilizable or nontoxic salts. Of compounds of the formula I which contain acidic groups, for example carboxylic acid groups, such salts are, for example, alkali metal salts or alkaline earth metal salts, such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts, such as, for example, salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example triethylamine, ethanolamine, tris(2-hydroxyethyl)amine, xcex1,xcex1,xcex1-tris(hydroxymethyl)methylamine or with amino acids, in particular basic amino acids.
Compounds of the formula I which contain basic groups, for example an amino group, amidino group or guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which contain both acidic groups and basic groups can also be present in the form of internal salts or betaines, which are also included by the present invention.
Salts can be obtained from the compounds of the formula I according to customary procedures known to the person skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent or dispersant, or alternatively from other salts by anion exchange or cation exchange.
The compounds of the formula I can be present in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these can independently of one another have the S configuration or the R configuration. The invention includes all possible stereoisomers of the compounds of the formula I, for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. The invention thus relates to enantiomers in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. The invention likewise relates to diastereomers in diastereomerically pure form and in the form of mixtures in all ratios. In the presence of cis/trans isomerism, the invention relates to both the cis form and the trans form and mixtures of these forms in all ratios. Individual stereoisomers can be prepared, if desired, by use of stereochemically homogeneous starting substances in the synthesis, by stereoselective synthesis or by separation of a mixture according to customary methods, for example by chromatography or crystallization, in the case of enantiomers, for example, by chromatography on chiral phases. If appropriate, derivatization can be carried out before separation of stereoisomers. A stereoisomer mixture can be separated at the stage of the compounds of the formula I or at the stage of a starting substance or of an intermediate in the course of the synthesis.
The compounds of the formula I according to the invention can moreover contain mobile hydrogen atoms, i.e. be present in various tautomeric forms. The present invention also relates to all tautomers of the compounds of the formula I. The present invention furthermore includes derivatives of compounds of the formula I, for example, solvates such as hydrates and adducts with alcohols, esters, prodrugs and other physiologically tolerable derivatives of compounds of the formula I, as well as active metabolites of compounds of the formula I. The invention relates in particular to prodrugs of the compounds of the formula I which are converted into compounds of the formula I under physiological conditions. Suitable prodrugs of the compounds of the formula I. i.e. chemically modified derivatives of the compounds of the formula I having improved properties as desired, are known to the person skilled in the art. More detailed information on prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130, Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350, each incorporated herein by reference in their entirety. Suitable prodrugs of the compounds of the formula I are especially ester prodrugs of carboxylic acid groups, amid prodrugs of carboxylic acid groups and alcohol prodrugs of carboxylic acid groups as well as acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups, amidino groups and guanidino groups. In the acyl prodrugs or carbamate prodrugs, a hydrogen atom situated on a nitrogen atom is replaced by an acyl group or carbamate group. Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups Rpxe2x80x94CO and RpaOxe2x80x94CO, in which Rp is hydrogen, (C1-C18)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, heteroaryl or heteroaryl-(C1-C8)-alkyl and Rpa has the meanings indicated for Rp with the exception of hydrogen.
The individual structural elements in the formula I preferably, for example, have the following meanings which they can have independently of one another. Radicals occurring more than once can have the meanings independently of one another and can in all cases be identical or different.
W is preferably a divalent radical selected from the group of R1xe2x80x94Axe2x80x94C(R13) and 
xe2x80x83in which the ring systems 
xe2x80x83can contain one or two identical or different heteroatoms selected from the group of N and O, can be saturated or monounsaturated and can be substituted by 1 or 2 identical or different substituents R13 and/or by one or two doubly bonded oxygen atoms, and in which L is C(R13) or N and in which m1 and m2 independently of one another are one of the numbers 0, 1, 2, 3 and 4, but the sum m1+m2 is one of the numbers 1, 2, 3 or 4, in particular one of the numbers 1, 3 or 4. W is particularly preferably the divalent radical R1xe2x80x94Axe2x80x94C(R13), in which R13 has the meanings indicated above. W is very particularly preferably the divalent radical R1xe2x80x94Axe2x80x94C(R13), in which R13 has the meanings indicated above, but is other than hydrogen. Specific groups of this type are, for example, the divalent radicals di((C1-C4)-alkyl)methylene ((C1-C4)-alkyl)2C less than , dimethylmethylene (CH3)2C less than  and (methyl)(phenyl)methylene (CH3)(C6H5)C less than . If W is the radical 
xe2x80x83a number of groups of this type is formed by the carbocyclic groups of the formula (CH2)m3C less than , which are optionally substituted as indicated, in which the number m3 of the polymethylene chain bonded to the spiro carbon atom C less than  via the terminal groups is 2, 3, 4, 5 or 6. Specific groups W of this type are, for example, the divalent radicals 1,1-cyclopropylidene (=dimethylenemethylene), 1,1-cyclopentylidene (=tetramethylenemethylene) and 1,1-cyclohexylidene (=pentamethylenemethylene), i.e. the radicals 
xe2x80x83in which the free bonds are symbolized by the line having a dot at the end, where the radicals derived from the 5-membered ring and from the 6-membered ring can in each case carry a doubly bonded oxygen atom as a substituent. On the whole, compounds of the formula I in which W has a meaning other than CH2 form a group of preferred compounds.
Y is preferably a carbonyl group or thiocarbonyl group, particularly preferably a carbonyl group.
A is preferably a direct bond, one of the divalent radicals (C1-C6)-alkylene, in particular (C1-C4)-alkylene, (C5-C6)-cycloalkylene, phenylene, phenylene-(C1-C4)-alkyl, in particular phenylene-(C1-C2)-alkyl, or a divalent radical of a 5-membered or 6-membered saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur. Particularly preferably, A is a direct bond or one of the divalent radicals (C1-C4)-alkylene, phenylene and phenylene-(C1-C2)-alkyl. If W is the radical R1xe2x80x94Axe2x80x94C(R13, a number of preferred radicals R1xe2x80x94Axe2x80x94 is formed from the radicals (C1-C4)-alkyl, optionally substituted phenyl and phenyl-(C1-C2)-alkyl optionally substituted in the phenyl radical, in particular from the radicals (C1-C4)-alkyl and optionally substituted phenyl.
B is preferably a divalent methylene radical or ethylene radical (=1,2-ethylene), where the methylene radical and the ethylene radical are unsubstituted or substituted by one or more identical or different radicals selected from the group of (C1-C8)-alkyl, in particular (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, in particular (C3-C6)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, in particular (C3-C6)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, in particular optionally substituted (C6-C10)-aryl, (C6-C14)-aryl(C1-C6)-alkyl optionally substituted in the aryl radical, in particular (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical. Particularly preferably, B is a substituted methylene radical or ethylene radical of this type, in particular a substituted methylene radical of this type. If an alkylene radical or alkenylene radical representing B is monosubstituted or polysubstituted, it is preferably monosubstituted, disubstituted or trisubstituted, particularly preferably monosubstituted or disubstituted, in particular monosubstituted. If a methylene radical or ethylene radical representing B is substituted, it is preferably substituted by one or two identical or different radicals, in particular by one radical selected from the group of (C1-C8)-alkyl, in particular (C1-C6)-alkyl, i.e., straight-chain or branched alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and (C3-C6)-cycloalkyl-(C1-C2)-alkyl.
E is preferably tetrazolyl, R6CO, R7CO, R10CO, HCO, R8Oxe2x80x94CH2, R8COxe2x80x94Oxe2x80x94CH2 or (R8O)2P(O)xe2x80x94Oxe2x80x94CH2, particularly preferably tetrazolyl, R10CO, R8Oxe2x80x94CH2, R8COxe2x80x94Oxe2x80x94CH2 or (R8O)2P(O)xe2x80x94Oxe2x80x94CH2, very particularly preferably R10CO, R8Oxe2x80x94CH2 or R8COxe2x80x94Oxe2x80x94CH2. A radical R8Oxe2x80x94CH2 representing the group E is preferably the hydroxymethyl radical HOxe2x80x94CH2. Especially preferably, E is R10CO, HOxe2x80x94CH2 or R8COxe2x80x94Oxe2x80x94CH2.
The radicals R preferably independently of one another are hydrogen or (C1-C8)-alkyl, in particular hydrogen, methyl or ethyl. They can be identical or different.
R2 is preferably hydrogen or (C1-C8)-alkyl, in particular (C1-C6)-alkyl, particularly preferably hydrogen, methyl or ethyl.
R3 is preferably hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 8 fluorine atoms, optionally substituted (C6-C12)-aryl, (C6-C12)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C6)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, COOR21, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15. Particularly preferably, R3 is hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalklyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C4)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C4)-alkyl, R11NH, COOR21, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15. Very particularly preferably, R3 is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, R11NH, COOR21, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15. Especially preferably, R3 is, for example, (C1-C8)-alkyl, in particular (C1-C4)-alkyl, for example methyl which can optionally be substituted by 1 to 6 fluorine atoms, (C6-C10)-aryl, in particular phenyl which can be unsubstituted or substituted, or CONHR4.
R4 is preferably (C1-C8)-alkyl which is unsubstituted or is substituted as indicated above in the definition of R4. Particularly preferably, R4 is (C1-C8)-alkyl, in particular (C1-C6)-alkyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C6)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO tetrazolyl, trifluoromethyl. It is very particularly preferred if one of the substituents in the alkyl group representing R4 is bonded in the 1-position of the alkyl group, i.e., to that carbon atom of the alkyl group to which there is also bonded the nitrogen atom in the group CONHR4 or in the group CON(CH3)R4, and if this substituent in the 1-position is of one of the radicals hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxycarbonyl which can also be substituted in the aryl radical, R6xe2x80x94CO, R7xe2x80x94CO, (C1-C6)-alkoxycarbonyl or tetrazolyl. In this very particularly preferred case, the radical xe2x80x94NHR4 or the radical xe2x80x94N(CH3)R4 is then the radical of an xcex1-amino acid or of an N-methyl-xcex1-amino acid or of a derivative thereof, where the radical of the amino acid is formally obtained by abstraction of a hydrogen atom from the amino group of the amino acid (if the substituent in the 1-position is the group R6xe2x80x94CO, the radical xe2x80x94NHR4 or the radical xe2x80x94N(CH3)R4 is correspondingly the radical of a dipeptide, tripeptide, tetrapeptide or pentapeptide). Especially preferred xcex1-amino acids are in this case those having a lipophilic side chain, for example phenylglycine, phenylalanine, valine, leucine, isoleucine and homologs thereof, as well as derivatives of these amino acids such as esters, amides or the derivatives in which the carboxylic acid group is converted into the radical R6xe2x80x94CO or R7xe2x80x94CO.
R5 is preferably optionally substituted ((C6-C12)-aryl, in particular optionally substituted (C6-C10)-aryl, especially optionally substituted phenyl.
R8 is preferably hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C12)-aryl or (C6-C12)-aryl-(C1-C8)-alkyl which can also be substituted in the aryl radical, particularly preferably hydrogen, (C1-C6)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C6)-alkyl which can also be substituted in the aryl radical, very particularly preferably hydrogen, (C1-C6)-alkyl or phenyl-(C1-C4)-alkyl optionally substituted in the phenyl radical. R8a preferably has one of the preferred meanings of R8 with the exception of hydrogen.
R10 is preferably hydroxyl, (C1-C8)-alkoxy, (C6-C12)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C12)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C12)-aryl-(C1-C6)-alkylcarbonyoxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy, (C6-C12)-aryl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, amino, mono- or di-((C1-C8)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy, (mono- or di-((C1-C8)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy, (mono- or di-((C6-C12)-aryl-(C1-C6)-alkyl))-amino)-carbonyl-(C1-C6)-alkoxy or (N-((C1-C8)-alkyl)-N-((C6-C12)-aryl-(C1-C6)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy all optionally substituted in the aryl radical. Particularly preferably, R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C10)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy, amino, mono- or di-((C1-C6)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy or (mono- or di-((C1-C6)-alkyl)-amino-carbonyl-(C1-C6)-alkoxy.
R11 is preferably hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2, particularly preferably hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, or R12axe2x80x94S(O)2, very particularly preferably R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, or R12axe2x80x94S(O)2.
R12a is preferably (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C5-C10)-cycloalkyl, (C5-C10)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15.
R13 is preferably hydrogen or (C1-C6)-alkyl, where a preferred alkyl radical represented by R13 is the methyl radical. Particularly preferably, R13 is (C1-C6)-alkyl, very particularly preferably (C1-C4)-alkyl, in particular methyl.
R15 is preferably R16xe2x80x94(C1-C3)-alkyl or R16, in particular R16xe2x80x94C1alkyl or R16.
R20 is preferably a direct bond or a divalent (C1-C4)-alkylene radical, particularly preferably a direct bond or a divalent (C1-C2)-alkylene radical, in particular a direct bond or a methylene radical or ethylene radical (1,2-ethylene), very particularly preferably a direct bond or a methylene radical.
R21 is preferably hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, the radical Het- or Het-(C1-C6)-alkyl, where alkyl radicals can be monosubstituted or polysubstituted by fluorine and the radicals R21, if they occur more than once, are independent of one another and can be identical or different. R21 is particularly preferably hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted in the aryl radical, where alkyl radicals can be monosubstituted or polysubstituted by fluorine. R21 is very particularly preferably hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C2)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C2)-alkyl optionally substituted in the aryl radical, where alkyl radicals can be monosubstituted or polysubstituted by fluorine, where again, if the radicals R21 occur more than once, they are independent of one another and can be identical or different.
R30 is preferably one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94COxe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94R31, R32xe2x80x94COxe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94R31 or R12axe2x80x94Oxe2x80x94COxe2x80x94N(R)xe2x80x94R31, in which n is 1 or 2. Particularly preferably, R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 or R32(R)Nxe2x80x94COxe2x80x94R31. Very particularly preferably, R30 is R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31 or R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, especially preferably R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, in particular R32NHxe2x80x94COxe2x80x94NHxe2x80x94R31.
R32 is preferably hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical. Particularly preferably, R32 is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical. Very particularly preferably, R32 is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical. A specifically preferred radical representing R32 is optionally substituted (C6-C10)-aryl, in particular unsubstituted phenyl or phenyl which is substituted by one or more identical or different substituents of the substituents on aromatics indicated above. If the radical R32 is bonded to a sulfur atom, it preferably has a meaning other than hydrogen.
R33 is preferably a direct bond or a divalent (C1-C4)-alkylene radical, particularly preferably a direct bond or a divalent (C1-C2)-alkylene radical, very particularly preferably a direct bond.
R34 is preferably a divalent radical selected from the group of (C1-C8)-alkylene, (C5-C10)-cycloalkylene, (C6-C12)-bicycloalkylene, optionally substituted (C6-C14)-arylene and optionally substituted heteroarylene, particularly preferably a divalent radical selected from the group of (C1-C6)-alkylene, (C5-C6)-cycloalkylene, optionally substituted (C6-C12)-arylene and optionally substituted heteroarylene, very particularly preferably a divalent radical from the group consisting of (C1-C6)-alkylene, optionally substituted (C6-C10)-arylene and optionally substituted heteroarylene, moreover preferably a divalent radical selected from the group of (C1-C4)-alkylene and optionally substituted (C6-C10)-arylene.
R35 is preferably a direct bond or a divalent (C1-C4)-alkylene radical, particularly preferably a direct bond or a divalent (C1-C2)-alkylene radical, in particular a direct bond or methylene or ethylene (1,2-ethylene), very particularly preferably (C1-C2)-alkylene (methylene or ethylene).
R36 is preferably a direct bond.
R31 is preferably a divalent radical xe2x80x94R33xe2x80x94R34xe2x80x94R35xe2x80x94R36xe2x80x94, in which one or more of the radicals R33, R34, R35 and R36 have preferred meanings. Particularly preferably, R31 is a divalent radical selected from the group of (C1-C8)-alkylene, (C5-C6)-cycloalkylene, (C5-C6)-cycloalkylene-(C1-C6)-alkyl, optionally substituted (C6-C10)-arylene, (C6-C10)-arylene-(C1-C6)-alkyl optionally substituted in the arylene radical, optionally substituted heteroarylene, heteroarylene-(C1-C6)-alkyl optionally substituted in the heteroarylene radical, (C1-C8)-alkylene-CO, optionally substituted (C6-C10)-arylene-CO, (C6-C10)-arylene-(C1-C6)-alkyl-CO optionally substituted in the arylene radical, optionally substituted heteroarylene-CO, heteroarylene-(C1-C6)-alkyl-CO optionally substituted in the heteroarylene radical, optionally substituted (C6-C10)-arylene-S(O)n, (C6-C10)-arylene-(C1-C6)-alkyl-S(O)n optionally substituted in the arylene radical, optionally substituted heteroarylene-S(O)n and heteroarylene-(C1-C6)-alkyl-S(O)n optionally substituted in the heteroarylene radical, in which n is 1 or 2, and where the CO group and the S(O)n group are bonded to the nitrogen atom in the imidazolidine ring in the formula I and, in the case of the radicals cycloalkylenealkyl, arylenealkyl and heteroarylenealkyl, the allyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I. Very particularly preferably, R31 is a divalent radical selected from the group of (C1-C6)-alkylene, optionally substituted (C6-C10)-arylene and (C6-C10)-arylene-(C1-C4)-alkyl optionally substituted in the aryl radical, where in the case of the arylenealkyl radical, the alkyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I. Moreover, R31 is preferably a divalent radical selected from the group of (C1-C6)-alkylene and (C6-C10)-arylene-(C1-C4)-alkyl optionally substituted in the aryl radical, in particular (C6-C10)-arylene-(C1-C2)-alkyl, where in the case of the arylenealkyl radical, the alkyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I. Especially preferably, R31 is the divalent radical phenylenemethyl-C6H4xe2x80x94CH2xe2x80x94, in particular the radical -1,4-phenylenemethyl-, in which the methyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I.
If R3 is hydrogen or one of the radicals (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, COOR21, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15, e is preferably 0 and h is preferably 1. If R3 is R11NH, e is preferably 1 and h is preferably 0. Compounds of the formula I in which e is 0 and h is 1 form a preferred group of compounds. In these preferred compounds, the group xe2x80x94NRxe2x80x94[C(R)(R)]hxe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E in the formula I is particularly preferably the group xe2x80x94NHxe2x80x94CH(R3)xe2x80x94CH2xe2x80x94E.
Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings or one specific of the preferred meanings mentioned, all combinations of preferred meanings of radicals being a subject of the present invention.
A particularly preferred group of compounds are compounds of the formula I in which
W is a divalent radical selected from the group of R1xe2x80x94Axe2x80x94C(R13), R1xe2x80x94Axe2x80x94C(R13)xe2x95x90C, 
xe2x80x83where the ring systems 
xe2x80x83can contain one or two identical or different heteroatoms selected from the group of N, O and S, can be saturated or monounsaturated or polyunsaturated and can be substituted by 1, 2 or 3 identical or different substituents R13 and/or by one or two doubly bonded oxygen atoms and/or sulfur atoms, and where L is C(R13) or N and where m1 and m2 independently of one another are one of the numbers 0, 1, 2, 3, 4, 5 and 6, the sum m1+m2, however, is one of the numbers 1, 2, 3, 4, 5 or 6;
Y is a carbonyl group, thiocarbonyl group or methylene group;
A is a direct bond, one of the divalent radicals (C1-C6)-alkylene, (C3-C7)-cycloalkylene, phenylene, phenylene-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl or a divalent radical of a 5-membered or 6-membered, saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur, where in the radicals phenylenealkyl and phenylenealkenyl, the radical R1 is bonded to the phenylene group;
B is a divalent radical selected from the group of (C1-C6)-alkylene, (C2-C6)-alkenylene, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alkylenephenyl and (C1-C3)-alkylenephenyl-(C1-C3)-alkyl, where the (C1-C6)-alkylene radical and the (C2-C6)-alkenylene radical are unsubstituted or are substituted by one or more identical or different radicals selected from the group of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is tetrazolyl, (R8O)2P(O), R10OS(O)2, R9NHS(O)2, R6CO, R7CO or R10CO;
R is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl, where all radicals R are independent of one another and the radicals R can be identical or different;
R1 is hydrogen, (C1-C10)-alkyl, which can optionally be monosubstituted or polysubstituted by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, R21xe2x80x94((C6-C14)-aryl) optionally substituted in the aryl radical, (R21xe2x80x94((C6-C14)-aryl))xe2x80x94(C1-C8)-alkyl optionally substituted in the aryl radical, the radical Het-, Het-(C1-C8)-alkyl or one of the radicals Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94R20xe2x80x94, X1xe2x80x94NHxe2x80x94R20xe2x80x94, R21Oxe2x80x94R20xe2x80x94, R21N(R21)xe2x80x94R20xe2x80x94, R21C(O)xe2x80x94, R21Oxe2x80x94C(O)xe2x80x94, R22N(R21)xe2x80x94C(O)xe2x80x94, R22C(O)xe2x80x94N(R21)xe2x80x94, R21Oxe2x80x94Nxe2x95x90, Oxe2x95x90 and Sxe2x95x90;
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C10)-alkycarbonyloxy-(C1-C6)-alkoxycarbonyl, optionally substituted (C6-C14)-arylcarbonyl, optionally substituted (C6-C14)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl which can also be substituted in the aryl radical, cyano, hydroxyl, (C1-C6)-alkoxy, (C6-C14)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, or amino;
X1 has one of the meanings of X or is Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), where Rxe2x80x2 and Rxe2x80x3 independently of one another have the meanings of X;
R2 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
R3 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, CON(CH3)R4, CONHR4, COOR21, COOR15, CON(CH3)R15 or CONHR15;
R4 is hydrogen or (C1-C10)-alkyl which is unsubstituted or monosubstituted or polysubstituted by identical or different radicals selected from the group of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C10)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or a radical of an optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially saturated or completely saturated and which can contain one, two or three identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally Nxe2x80x94(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid, which can also be substituted in the aryl radical, or the radical of a dipeptide, tripeptide or tetrapeptide as well as their esters and amides, where free functional groups can be protected by protective groups customary in peptide chemistry and where the nitrogen atoms in the amide bonds in the group R6xe2x80x94CO can carry a radical R as a substituent;
R7 is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, where additional ring nitrogen atoms can carry identical or different radicals selected from the group of hydrogen, Rh, HCO, RhCO, RhOxe2x80x94CO, HOxe2x80x94COxe2x80x94(C1-C4)-alkyl and RhOxe2x80x94COxe2x80x94(C1-C4)-alkyl as substituents and Rh is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
R8 is hydrogen, (C1-C10)-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl which can also be substituted in the aryl radical, where the radicals R8 are independent of one another:
R9 is hydrogen, aminocarbonyl, (C1-C10)-alkylaminocarbonyl, (C3-C8)-cyclo-alkylaminocarbonyl, optionally substituted (C6-C14)-arylaminocarbonyl, (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C6)-cycloalkyl;
R10 is hydroxyl, (C1-C10)-cycloalkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-arylcarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, amino or mono- or di-((C1-C10)-alkyl)-amino;
R11 is hydrogen, R12a, R12axe2x80x94CO, Hxe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS, R12axe2x80x94S(O)2 or R12bxe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkyl)-amino or R12axe2x80x94NH:
R13 is hydrogen, (C1-C6)-alkyl which can optionally be monosubstituted or polysubstituted by fluorine, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl or (C3-C8)-cyclo-(C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 24-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl and oxo;
R20 is a direct bond or a divalent (C1-C6)-alkylene radical;
R21 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted in the aryl radical, the radical Het- or Het-(C1-C8)-alkyl, where alkyl radicals can be monosubstituted or polysubstituted by fluorine and the radicals R21, if they occur more than once, are independent of one another and can be identical or different;
R22 is R21xe2x80x94, R21Oxe2x80x94, R21N(R21)xe2x80x94, R21C(O)xe2x80x94, R21Oxe2x80x94C(O)xe2x80x94, R21N(R21)xe2x80x94C(O)xe2x80x94, R21N(R21)xe2x80x94C(xe2x95x90N(R21))xe2x80x94 or R21C(O)xe2x80x94N(R21)xe2x80x94;
R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94COxe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94R31, R32xe2x80x94COxe2x80x94R31, R32xe2x80x94CSxe2x80x94R31 or R32xe2x80x94S(O)nxe2x80x94R31, where R30 cannot be R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 if at the same time W is R1xe2x80x94Axe2x80x94C(R13), A is a direct bond and R1 and R13 are hydrogen;
R31 is the divalent radical xe2x80x94R33xe2x80x94R34xe2x80x94R35xe2x80x94R36xe2x80x94, where R36 is bonded to the nitrogen atom in the imidazolidine ring in the formula I;
R32 is hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical;
R33 is a direct bond or a divalent (C1-C6)-alkylene radical;
R34 is a divalent radical selected from the group of (C1-C8)-alkylene, (C3-C12)-cycloalkylene, (C6-C12)-bicycloalkylene, (C6-C12)-tricycloalkylene, optionally substituted (C6-C14)-arylene and optionally substituted heteroarylene;
R35 is a direct bond or a divalent (C1-C8)-alkylene radical;
R36 is a direct bond, the group xe2x80x94COxe2x80x94 or the group xe2x80x94S(O)nxe2x80x94;
Het is a radical of a monocyclic or polycyclic 4-membered to 14-membered, aromatic or nonaromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms from the group consisting of N, O and S as ring members and which can optionally be substituted by one or more identical or different substituents;
e and h independently of one another are 0 or 1;
n is 1 or 2, where the numbers n, if they occur more than once, are independent of one another and can be identical or different;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further particularly preferred group of compounds is formed by compounds of the formula I in which
W is a divalent radical selected from the group of R1xe2x80x94Axe2x80x94C(R13), R1xe2x80x94Axe2x80x94C(R13)xe2x95x90C, 
xe2x80x83in which the ring systems 
xe2x80x83can contain one or two identical or different heteroatoms selected from the group of N and O, can be saturated or monounsaturated and can be substituted by 1 or 2 identical or different substituents R13 and/or by one or two doubly bonded oxygen atoms, and in which L is C(R13) or N and in which m1 and m2 independently of one another are one of the numbers 0, 1, 2, 3, 4 and 5, the sum m1+m2, however, is one of the numbers 1, 2, 3, 4 and 5;
Y is a carbonyl group or thiocarbonyl group;
A is a direct bond, one of the divalent radicals (C1-C6)-alkylene, (C3-C7)-cycloalkylene, phenylene, phenylene-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl or a divalent radical of a 5-membered or 6-membered, saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur, where in the radicals phenylenealkyl and phenylenealkenyl the radical R1 is bonded to the phenylene group;
B is a divalent methylene radical or ethylene radical, where the methylene radical and the ethylene radical are unsubstituted or are substituted by one or more identical or different radicals selected from the group of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is tetrazolyl, R10CO, R8Oxe2x80x94CH2, R8COxe2x80x94Oxe2x80x94CH2 or (R8O)2P(O)xe2x80x94Oxe2x80x94(CH2;
R is hydrogen, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical, where all radicals R are independent of one another and the radicals R can be identical or different;
R1 is hydrogen, (C1-C10)-alkyl, which can optionally be monosubstituted or polysubstituted by fluorine, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, R21xe2x80x94((C6-C14)-aryl) optionally substituted in the aryl radical, (R21xe2x80x94((C6-C14)-aryl))xe2x80x94(C1-C8)-alkyl optionally substituted in the aryl radical, the radical Het-, Het-(C1-C8)-alkyl or one of the radicals Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94R20xe2x80x94, X1xe2x80x94NHxe2x80x94R20xe2x80x94, R21Oxe2x80x94R20xe2x80x94, R22C(O)xe2x80x94N(R21)xe2x80x94, R22N(R21)xe2x80x94C(O)xe2x80x94, R21Oxe2x80x94Nxe2x95x90, Oxe2x95x90 and Sxe2x95x90;
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C10)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, optionally substituted (C6-C14)-arylcarbonyl, optionally substituted (C6-C14)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl which can also be substituted in the aryl radical, hydroxyl, (C1-C6)-alkoxy, (C6-C14)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, or amino;
X1 has one of the meanings of X or is Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), in which Rxe2x80x2 and Rxe2x80x3 independently of one another have the meanings of X;
R2 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
R3 is hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 8 fluorine atoms, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, COOR21, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15;
R4 is hydrogen or (C1-C8)-alkyl which is unsubstituted or monosubstituted or polysubstituted by identical or different radicals selected from the group of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C10)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or a radical of an optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially saturated or completely saturated and which can contain one, two or three identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally Nxe2x80x94(C1-C8)-alkylated or Nxe2x80x94((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid, which can also be substituted in the aryl radical, or the radical of a dipeptide, tripeptide or tetrapeptide, as well as their esters and amides, in which free functional groups can be protected by protective groups customary in peptide chemistry and in which the nitrogen atoms in the amide bonds in the group R6xe2x80x94CO can carry a radical R as a substituent;
R7 is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, in which additional ring nitrogen atoms can carry identical or different radicals selected from the group of hydrogen, Rh, HCO, RhCO, RhOxe2x80x94CO, HOxe2x80x94COxe2x80x94(C1-C4)-alkyl and RhOxe2x80x94COxe2x80x94(C1-C4)-alkyl as substituents and Rh is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
R8 is hydrogen, (C1-C6)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C6)-alkyl which can also be substituted in the aryl radical;
R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C12)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C12)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C12)-aryl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy, (C6-C12)-aryl-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy optionally substituted in the aryl radical, amino, mono- or di-((C1-C8)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy, (mono- or di-((C1-C8)-alkyl)-amino)carbonyl-(C1-C6)-alkoxy, (mono- or di-((C6-C12)-aryl-(C1-C6)-alkyl))-amino)-carbonyl-(C1-C6)-alkoxy or (N-((C1-C8)-alkyl)-N-((C6-C12)-aryl-(C1-C6)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy both optionally substituted in the aryl radical;
R11 is hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C5-C10)-cycloalkyl, (C5-C10)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkylamino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C6)-alkyl;
R15 is R16(C1-C6)-alkyl or R16;
R16 is a 6-membered to 14-membered, bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group of (C1-C4)-alkyl and oxo;
R20 is a direct bond or (C1-C4)-alkylene;
R21 is hydrogen, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, the radical Het- or Het-(C1-C6)-alkyl, where alkyl radicals can be monosubstituted or polysubstituted by fluorine and the radicals R21, if they occur more than once, can be identical or different;
R22 is one of the radicals R21xe2x80x94, R21N(R21)xe2x80x94, R21C(O)xe2x80x94, R21Oxe2x80x94C(O)xe2x80x94 or R21N(R21)xe2x80x94C(xe2x95x90N(R21))xe2x80x94;
R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94COxe2x80x94R31, R32(R)Nxe2x80x94S(O)nxe2x80x94R31, R32xe2x80x94COxe2x80x94R31, R32xe2x80x94S(O)nxe2x80x94R31 or R12axe2x80x94Oxe2x80x94COxe2x80x94N(R)xe2x80x94R31, where R30 cannot be R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 if at the same time W is R1xe2x80x94Axe2x80x94C(R13), A is a direct bond and R1 and R13 are hydrogen;
R31 is the divalent radical xe2x80x94R33xe2x80x94R34xe2x80x94R35xe2x80x94R36xe2x80x94, where R36 is bonded to the nitrogen atom in the imidazolidine ring in the formula I;
R32 is hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical;
R33 is a direct bond or a divalent (C1-C6)-alkylene radical;
R34 is a divalent radical selected from the group of (C1-C8)-alkylene, (C5-C10)-cycloalkylene, (C6-C12)-bicycloalkylene, optionally substituted (C6-C14)-arylene and optionally substituted heteroarylene:
R35 is a direct bond or a divalent (C1-C8)-alkylene radical;
R36 is a direct bond, the group xe2x80x94COxe2x80x94 or the group xe2x80x94S(O)nxe2x80x94;
Het is a radical of a monocyclic or polycyclic, 5-membered to 12-membered, aromatic or nonaromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms selected from the group of N and O as ring members and which can optionally be substituted by one or more, identical or different substituents;
e and h independently of one another are 0 or 1;
n is 1 or 2, where the numbers n, if they occur more than once, are independent of one another and can be identical or different;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Very particularly preferred compounds of the formula are those compounds in which
W is a divalent radical selected from the group of R1xe2x80x94Axe2x80x94C(R13) and 
xe2x80x83in which the ring systems 
xe2x80x83can contain one or two identical or different heteroatoms selected from the group of N and O, can be saturated or monounsaturated and can be substituted by 1 or 2 identical or different substituents R13 and/or by one or two doubly bonded oxygen atoms, and in which L is C(R13) or N and in which m1 and m2 independently of one another are one of the numbers 0, 1, 2, 3 and 4, the sum m1+m2, however, is one of the numbers 1, 2, 3 and 4;
Y is a carbonyl group or thiocarbonyl group;
A is a direct bond, one of the divalent radicals (C1-C6)-alkylene, (C5-C6)-cycloalkylene, phenylene, phenylene-(C1-C4)-alkyl or a divalent radical of a 5-membered or 6-membered, saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur, where in the radicals phenylenealkyl and phenylenealkenyl the radical R1 is bonded to the phenylene group;
B is a divalent methylene radical or ethylene radical where the methylene radical and the ethylene radical are unsubstituted or are substituted by one or two identical or different radicals selected from the group of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is R10CO, HOxe2x80x94CH2 or R8COxe2x80x94Oxe2x80x94CH2;
R is hydrogen or (C1-C8)-alkyl, where all radicals R are independent of one another and the radicals R can be identical or different;
R1 is hydrogen, (C1-C10)-alkyl, which can optionally be monosubstituted or polysubstituted by fluorine, R21xe2x80x94((C6-C10)-aryl) optionally substituted in the aryl radical, (R21xe2x80x94((C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, the radical Het-, Het-(C1-C6)-alkyl or one of the radicals Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94R20, X1xe2x80x94NHxe2x80x94R20xe2x80x94, R22N(R21)xe2x80x94C(O)xe2x80x94, Oxe2x95x90 and Sxe2x95x90;
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, optionally substituted (C6-C10)-arylcarbonyl, optionally substituted (C6-C10)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl which can also be substituted in the aryl radical, hydroxyl, (C1-C6)-alkoxy, or amino;
X1 has one of the meanings of X or is Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), in which Rxe2x80x2 and Rxe2x80x3 independently of one another have the meanings of X;
R2 is hydrogen or (C1-C8)-alkyl;
R3 is hydrogen, (C1-C8)-alkyl, which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C6)-cycloalkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, COOR21, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15;
R4 is (C1-C8)-alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different radicals selected from the group of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C6)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C12)-aryl, (C6-C12)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or a radical of an optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially saturated or completely saturated and which can contain one, two or three identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkylated or N-((C6-C12)-aryl-(C1-C8)-alkylated) azaamino acid, which can also be substituted in the aryl radical, or the radical of a dipeptide or tripeptide, as well as their esters and amides, in which free functional groups can be protected by protective groups customary in peptide chemistry and in which the nitrogen atoms in the amide bonds in the group R6xe2x80x94CO can carry a radical R as a substituent;
R7 is the radical of a 5-membered to 7-membered, saturated monocyclic or bicyclic heterocycle bonded via a nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, in which additional ring nitrogen atoms can carry identical or different radicals selected from the group of hydrogen, Rh, HCO, RhCO, RhOxe2x80x94CO, HOxe2x80x94COxe2x80x94(C1-C4)-alkyl and RhOxe2x80x94COxe2x80x94(C1-C4)-alkyl as substituents and Rh is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical;
R8 is hydrogen, (C1-C6)-alkyl or phenyl-(C1-C4)-alkyl optionally substituted in the phenyl radical,
R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C10)-aryloxy, (C1-C6)-alkylcarbonyloxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy, amino, mono- or di-((C1-C6)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy or (mono- or di-((C1-C6)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy;
R11 is hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO or R12axe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C5-C10)-cycloalkyl, (C5-C10)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 14-membered, bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group of (C1-C4)-alkyl and oxo;
R20 is a direct bond or (C1-C2)-alkylene;
R21 is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, the radical Het- or Het-(C1-C4)-alkyl, where alkyl radicals can be monosubstituted or polysubstituted by fluorine and the radicals R21, if they occur more than once, can be identical or different;
R22 is one of the radicals R21xe2x80x94, R21N(R21)xe2x80x94 or R21N(R21)xe2x80x94C(xe2x95x90N(R21))xe2x80x94;
R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31, R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 or R32(R)Nxe2x80x94COxe2x80x94R31, where R30 cannot be R32xe2x80x94COxe2x80x94N(R)xe2x80x94R31 if at the same time W is R1xe2x80x94Axe2x80x94C(R13), A is a direct bond and R1 and R13 are hydrogen;
R31 is the divalent radical xe2x80x94R33xe2x80x94R34xe2x80x94R35xe2x80x94R36xe2x80x94, where R36 is bonded to the nitrogen atom in the imidazolidine ring in the formula I;
R32 is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
R33 is a direct bond or a divalent (C1-C4)-alkylene radical;
R34 is a divalent radical selected from the group of (C1-C6)-alkylene, (C5-C6)-cycloalkylene, optionally substituted (C6-C10)-arylene and optionally substituted heteroarylene;
R35 is a direct bond or a divalent (C1-C4)-alkylene radical;
R36 is a direct bond, the group xe2x80x94COxe2x80x94 or the group xe2x80x94S(O)nxe2x80x94;
Het is a radical of a monocyclic or polycyclic, 5-membered to 12-membered, aromatic or nonaromatic ring which contains 1 or 2 identical or different heteroatoms selected selected from the group of N and O as ring members and which can optionally be substituted by one or more, identical or different substituents;
e and h independently of one another are 0 or 1;
n is 1 or 2;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Additionally preferred compounds of the formula I are those in which
W is the divalent radical R1xe2x80x94Axe2x80x94C(R13),
Y is a carbonyl group;
A is a direct bond, one of the divalent radicals (C1-C6)-alkylene, phenylene, phenylene-(C1-C2)-alkyl or a divalent radical of a 5-membered or 6-membered, saturated or unsaturated heterocycle which can contain one or two nitrogen atoms and can be monosubstituted or disubstituted by (C1-C6)-alkyl or doubly bonded oxygen or sulfur, where in the radicals phenylenealkyl and phenylenealkenyl the radical R1 is bonded to the phenylene group;
B is a divalent methylene radical or ethylene radical where the methylene radical and the ethylene radical are unsubstituted or are substituted by a radical selected from the group of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is R10CO, HOxe2x80x94CH2 or R8COxe2x80x94Oxe2x80x94CH2.
R is hydrogen or (C1-C8)-alkyl where all radicals R are independent of one another and the radicals R can be identical or different;
R1 is hydrogen, (C1-C10)-alkyl, which can optionally be monosubstituted or polysubstituted by fluorine, R21((C6-C10)-aryl) optionally substituted in the aryl radical, (R21((C6-C10)-aryl)-(C1-C6)-alkyl optionally substituted in the aryl radical, the radical Het-, Het-(C1-C4)-alkyl or one of the radicals Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94R20xe2x80x94, X1xe2x80x94NHxe2x80x94R20xe2x80x94, and Oxe2x95x90;
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, optionally substituted (C6-C10)-arylcarbonyl, optionally substituted (C6-C10)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl which can also be substituted in the aryl radical, hydroxyl, (C1-C6)-alkoxy or amino;
X1 has one of the meanings of X or is Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), in which Rxe2x80x2 and Rxe2x80x3 independently of one another have the meanings of X;
R2 is hydrogen or (C1-C6)-alkyl;
R3 is hydrogen, (C1-C8)-alkyl, which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-alkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C4)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, COOR21, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15;
R4 is (C1-C6)-alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different radicals selected from the group of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxycarbonyl, which can also be substituted in the aryl radical, (C1-C6)-alkoxycarbonyl, R6xe2x80x94CO, R7xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical or a radical of an optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially saturated or completely saturated and which can contain one, two or three identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur;
R6 is a radical of a natural or unnatural amino acid or the radical of a dipeptide or tripeptide, as well as their esters and amides, in which free functional groups can be protected by protective groups customary in peptide chemistry and in which the nitrogen atoms in the amide bonds in the group R6xe2x80x94CO can carry a radical R as a substituent;
R7 is the radical of a 5-membered to 7membered, saturated monocyclic heterocycle bonded via a nitrogen atom, which can contain one or two identical or different additional ring heteroatoms selected from the group of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, in which additional ring nitrogen atoms can carry identical or different radicals selected from the group of hydrogen, Rh, HCO, RhCO, RhOxe2x80x94CO, HOxe2x80x94COxe2x80x94(C1-C4)-alkyl and RhOxe2x80x94COxe2x80x94(C1-C4)-alkyl as substituents and Rh is (C1-C4)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-C1-C4)-alkyl optionally substituted in the aryl radical;
R8 is hydrogen, (C1-C6)-alkyl or phenyl-(C1-C4)-alkyl optionally substituted in the phenyl radical,
R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C10)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy, amino, mono- or di-((C1-C6)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy or (mono- or di-((C1-C6)-alkyl)-amino)-carbonyl)-(C1-C6)-alkoxy;
R11 is hydrogen R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, or R12axe2x80x94S(O)2;
R12a is (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C8)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 12-membered, bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group of (C1-C4)-alkyl and oxo;
R20 is a direct bond or methylene;
R21 is hydrogen, (C1-C6)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C2)-alkyl optionally substituted in the aryl radical, the radical Het- or Het-(C1-C2)-alkyl, where alkyl radicals can be monosubstituted to tetrasubstituted by fluorine and the radicals R21, if they occur more than once can be identical or different;
R30 is one of the radicals R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31 or R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31,
R31 is a divalent radical selected from the group of (C1-C6)-alkylene, optionally substituted (C6-C10)-arylene, (C6-C10)-arylene-(C1-C4)-alkyl optionally substituted in the arylene radical, (C5-C6)-cycloalkylene, (C5-C6)-cycloalkylene-(C1-C4)-alkyl, optionally substituted heteroarylene or heteroarylene-(C1-C4)-alkyl optionally substituted in the heteroarylene radical, where in the case of the arylenealkyl radical, of the cycloalkylenealkyl radical and of the heteroarylenealkyl radical the alkyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I;
R32 is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical;
Het is a radical of a monocyclic or polycyclic, 5-membered to 10-membered, aromatic or nonaromatic ring which contains 1 or 2 identical or different heteroatoms from the group consisting of N and O as ring members and which can optionally be substituted by one or more, identical or different substituents;
e and h independently of one another are 0or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A series of especially preferred compounds includes those compounds of the formula I in which B is unsubstituted methylene or methylene which is substituted by a (C1-C8)-alkyl radical, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly especially preferred in this series are compounds of the formula I in which B is methylene which is substituted by a (C1-C8)-alkyl radical, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which R30 is a radical selected from the group of R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31 and R32(R)Nxe2x80x94CSxe2x80x94N(R)xe2x80x94R31 and R31 is a divalent radical selected from the group of (C1-C6)-alkylene and (C6-C10)-arylene-(C1-C4)-alkyl optionally substituted in the arylene radical, where in the case of the arylenealkyl radical the alkyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. In this series, additionally preferred compounds of the formula I are those in which R30 is the radical R32NHxe2x80x94COxe2x80x94NHxe2x80x94R31 and therein R32 is optionally substituted phenyl and R31 is the divalent radical 1,4-phenylenemethyl (i.e. xe2x80x94(1,4-C6H4)xe2x80x94CH2xe2x80x94), in which the methyl group is bonded to the nitrogen atom in the imidazolidine ring in the formula I, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which R13 is hydrogen or methyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly especially preferred in this series are compounds of the formula I in which the group R1xe2x80x94Axe2x80x94 is not hydrogen and at the same time the group R13 is also not hydrogen, i.e. compounds in which W is not CH2, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, where it is very particularly especially preferred if, in these compounds, R13 is methyl, i.e., if compounds are present in which W is the divalent radical R1xe2x80x94Axe2x80x94C(CH3) and therein R1xe2x80x94Axe2x80x94 has a meaning other than hydrogen.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time the radicals R13 and R1xe2x80x94Axe2x80x94 are other than hydrogen, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)xe2x80x94CH2, in which the group xe2x80x94(1,4-C6H4)xe2x80x94 is a phenylene radical linked via the positions 1 and 4, and R32 is optionally substituted phenyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time the radicals R13 and R1xe2x80x94Axe2x80x94 are other than hydrogen, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)xe2x80x94CH2, R32 is optionally substituted phenyl and B is a divalent methylene radical which is unsubstituted orxe2x80x94in a preferred formxe2x80x94is substituted by (C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C2)-alkyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time the radicals R13 and R1xe2x80x94Axe2x80x94 are other than hydrogen, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)xe2x80x94CH2, R32 is optionally substituted phenyl, B is a divalent methylene radical which is unsubstituted orxe2x80x94in a preferred formxe2x80x94is substituted by (C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C2)-alkyl, and the radical xe2x80x94N(R)xe2x80x94[C(R)(R)]exe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E in the formula I is the radical xe2x80x94NHxe2x80x94CH(R3)xe2x80x94CH2xe2x80x94E, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time W is one of the divalent radicals 1,1-cyclopropylidene, 1,1-cyclopentylidene and 1,1-cyclohexylidene, which are explained in greater detail above, where the radicals derived from the 5-membered ring and from the 6-membered ring can in each case carry a doubly bonded oxygen atom as substituents, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)xe2x80x94CH2 and R32 is optionally substituted phenyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time W is one of the divalent radicals 1,1-cyclopropylidene, 1,1-cyclopentylidene and 1,1-cyclohexylidene, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)xe2x80x94CH2, R32 is optionally substituted phenyl and B is a divalent methylene radical which is unsubstituted orxe2x80x94in a preferred formxe2x80x94is substituted by (C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C2)-alkyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which at the same time W is one of the divalent radicals 1,1-cyclopropylidene, 1,1-cyclopentylidene and 1,1-cyclohexylidene, R30 is the radical R32xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(1,4-C6H4)-CH2, R32 is optionally subs d phenol, B is a divalent methylene radical which is unsubstituted orxe2x80x94in a preferred formxe2x80x94is substituted by (C1C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C2)-alkyl, and the radical xe2x80x94N(R)xe2x80x94[C(R)(R)]exe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)(R)]hxe2x80x94E in the formula I is the radical xe2x80x94NHxe2x80x94CH(R3)xe2x80x94CH2xe2x80x94E, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
A further series of especially preferred compounds includes those compounds of the formula I in which in the radical xe2x80x94N(R)xe2x80x94[(R)(R)]exe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E which is linked to the group xe2x80x94Bxe2x80x94COxe2x80x94 by an amide bond, the chain of carbon atoms between the group N(R) and the first group bonded to this chain which is an acid group such as a carboxylic acid group, sulfonic acid group, phosphonic acid group or tetrazolyl group or a derivative thereof such as an ester or an amide, comprises two or more than two carbon atoms, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. This first acid group (or the derivative thereof) which, starting from the group N(R), is bonded to this chain of carbon atoms can be the group E or can be the group R3, if the latter is, for example, COOR21, CONHR4, COR6, COR7 etc. Particularly especially preferred compounds in this series are those of the formula I in which, in the radical xe2x80x94N(R)xe2x80x94[C(R)(R)]exe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E, the chain of carbon atoms between the group N(R) and the first group bonded to this chain, which is an acid group or a derivative thereof, comprises exactly two carbon atoms, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly especially preferred compounds of the formula I of this type can be, for example, compounds in which e is 1, i.e., compounds which contain the group xe2x80x94N(R)xe2x80x94C(R)(R)xe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E, where in the case of these compounds h can be 1 or 0 and where it is preferred in the case of these compounds if R3 is R11NH and at the same time h is 0, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly especially preferred compounds of the formula I of this type can also be, for example, compounds in which e is 0, h is 1 and R3 is not an acid group or a derivative thereof, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, i.e. compounds which contain a radical xe2x80x94N(R)xe2x80x94C(R2)(R3a)xe2x80x94C(R)(R)xe2x80x94E, in which R3a is defined as R3, but cannot be a carboxylic acid group or a derivative thereof such as an ester or an amide. Preferably, in these compounds, R3a is hydrogen, (C1-C8)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl (C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkynyl. Particularly preferably, in these compounds, R3a is hydrogen, (C1-C6)-alkyl which can optionally be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, (C10-C12)-tricycloalkyl or (C10-C12)-tricycloalkyl-(C1-C4)-alkyl. It is furthermore preferred in the compounds of this series if the group xe2x80x94N(R)xe2x80x94 in the radical xe2x80x94N(R)xe2x80x94[C(R)(R)]exe2x80x94C(R2)(R3xe2x80x94[C(R)(R)]hxe2x80x94E is the group xe2x80x94NHxe2x80x94.
A further series of especially preferred compounds includes those compounds of the formula I in which in the radical xe2x80x94N(R)xe2x80x94[C(R)(R)]exe2x80x94C(R2)(R3)xe2x80x94[C(R)(R)]hxe2x80x94E the chain of carbon atoms between the group N(R) and the first group bonded to this chain, which is an acid group or a derivative thereof, only comprises one carbon atom, in all their stereoisomeric forms and mixtures thereof in all ratios and their physiologically tolerable salts, where, however, in these compounds the first acid group or the derivative thereof which, starting from the group N(R), is bonded to the chain of carbon atoms, must fulfil the following condition: a) the first acid group or the derivative thereof is an amide group which, however, in an alkyl substituent on the amide nitrogen does not contain a carboxylic acid group (or a derivative thereof such as an ester group or an amide group) bonded to this alkyl substituent, or b) the first acid group is a free acid group (or a salt thereof), or c) the first acid group or the derivative thereof is an ester group. Compounds of this series can be, for example, compounds of the formula I in which e is 0and R3 is COOR21, COOR15, CONHR15 or CON(CH3)R15, preferably CONHR15, and h is O or 1, preferably 1. Compounds of this series can also be, for example, compounds of the formula I in which e is O, h is O or 1, preferably 1, and R3is CON(CH3)R4 or CONHR4, but in which a (C1-C10)-alkyl radical representing R4 cannot be substituted by a carboxylic acid group or a derivative thereof such as an ester or an amide, i.e., for example, compounds in which R4 is hydrogen or in particular (C1-C10)-alkyl which is unsubstituted or substituted by one or more identical or different radicals from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, tetrazolyl and trifluoromethyl. In the compounds of this series, E is preferably an acid group or a derivative thereof.
Generally, compounds of the formula I are preferred which have a uniform configuration at one chiral centers or uniform configurations at more than one chiral centers, for example, when appropriately substituted, at the carbon atom carrying the radicals R2 and R3 and/or at the center W in the imidazolidine ring in the formula I. That means, compounds are preferred which are present in a uniform or essentially uniform configuration, either in R configuration or in S configuration, at one or more chiral centers and which are not present at such centers as an R/S mixture. The individual chiral centers in these compounds of the formula I can, however, independently of one another, have the R configuration or the S configuration and can have identical or different configurations.
The compounds of the formula I can be prepared, for example, by fragment condensation of a compound of the formula II 
with a compound of the formula III, 
where, in the formulae II and III, the groups W, Y, B, E, R, R2, R3, R30 as well as e and h are defined as indicated above or alternatively functional groups can be contained in protected form or in the form of precursors in these groups, and where G is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or activated carboxylic acid derivatives such as acid chlorides or active esters. If compounds of the formula I are to be prepared in which, for example, R3 in the formula I is a carboxylic acid derivative or contains such a group, it is also possible that in the compounds of the formula III the radical R3 initially is a hydroxycarbonyl group present in protected form or contains such a group, and that then the desired final group R3 is synthesized in one or more further steps only after the condensation of the compounds of the formulae II and III. Precursors of functional groups are groups which can be converted into the desired functional group according to the customary synthesis processes known to the person skilled in the art. For example, a nitro group can be converted into an amino group by reduction, for example by catalytic hydrogenation, and can be designated as a precursor for an amino group or a group obtainable therefrom by further reactions. A cyano group, which can be converted into an aminomethyl group by reduction or into an acid amide group or a carboxylic acid group by hydrolysis, can be designated as a precursor for these groups. An alcohol group, which can be oxidized to an aldehyde group or a ketone group, can be designated as a precursor for these groups. A precursor for a group, however, can also be a group from which a relatively large part of the target molecule is synthesized in several reaction steps carried out later. Examples of protective groups which are introduced into the molecule before carrying out a reaction or a reaction sequence and are later removed again, are mentioned above.
For the condensation of the compounds of the formula II with those of the formula III, the coupling methods of peptide chemistry well known per se to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974); incorporated by reference herein its entirety. Possible condensing agents or coupling reagents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, O-((cyano(ethoxy-carbonyl)-methylene)amino)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA).
The condensation can be carried out under the standard conditions well known to the person skilled in the art. Often, it is necessary in the condensation to protect nonreacting amino groups present by reversible protective groups. The same applies to carboxyl groups not involved in the reaction, which are preferably present during the condensation as (C1-C6)-alkyl esters, benzyl esters or tert-butyl esters. Amino group protection is unnecessary if the amino groups are still present in the form of precursors, for example as nitro groups or cyano groups, and are only formed after condensation, for example by hydrogenation. After condensation, the protective groups present are removed in a suitable manner. For example, NO2 groups (guanidino protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters can be removed by hydrogenation. The protective groups of the tert-butyl type are removed under acidic conditions, while the 9-fluorenylmethyloxycarbonyl radical is removed by secondary amines. The compounds of the formula I can also be prepared, for example, by synthesizing the compounds stepwise on a solid phase according to customary methods, where the individual structural elements of the molecule can be introduced in a different sequence.
Compounds of the formula II in which W is R1xe2x80x94Axe2x80x94C(R13) and Y is a carbonyl group can be prepared, for example, by first reacting compounds of the formula IV 
in a Bucherer reaction, for example with ammonium carbonate and potassium cyanide, to give compounds of the formula V 
(H. T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934), 5), where in the formulae IV and V the groups R1, R13 and A are defined as indicated above. Compounds of the formula VI 
in which R1, R13, A, B and G are defined as indicated above, can then be obtained by first reacting the compounds of the formula V, for example, with an alkylating reagent which introduces the radical xe2x80x94Bxe2x80x94G into the molecule. The reaction of compounds of the formula VI with a second reagent of the formula R30xe2x80x94LG, in which R30 has the meanings indicated above and LG is a nucleophilically substitutable leaving group, for example halogen, in particular chlorine or bromine. sulfonyloxy such as tosyloxy, methylsulfonyloxy or trifluoromethylsulfonyloxy, (C1-C4)-alkoxy, optionally substituted phenoxy or a heterocyclic leaving group such as, for example, imidazolyl, then leads to the corresponding compounds of the formula II.
Generally, depending on the meanings of the radical R30 and other radicals, it can also be advantageous not to introduce the final radical R30 into the molecule by means of the reagent R30xe2x80x94LG, but after linking a precursor of the group R30 to the imidazolidine ring, to synthesize the radical R30 on the imidazolidine ring. This can be carried out, for example, at the stage of a compound of the formula VI or the compound of the formula II prepared therefrom or at the stage of another intermediate of the synthesis. For example, this procedure is shown below on compounds in which R30 is the urea group R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31. Compounds of the formula II, in which R30 is R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31, can be prepared by this procedure, for example, by first reacting a compound of the formula VI with a reagent of the formula PGxe2x80x94N(R)xe2x80x94R31xe2x80x94LG, in which LG again a nucleophilically substitutable leaving group, to give a compound of the formula VII 
where PG is an amino protective group, for example tert-butoxycarbonyl or benzyloxycarbonyl, and where the meanings indicated above otherwise apply. After removing the protective group PG, compounds of the formula II in which R30 is R32NHxe2x80x94COxe2x80x94N(R)xe2x80x94R31 are then obtained by reaction of the resulting amino group HNRxe2x80x94 with, for example, an isocyanate of the formula R32xe2x80x94Nxe2x95x90Cxe2x95x90O. By reaction, for example, with a carbamoyl chloride of the formula R32(R)Nxe2x80x94COxe2x80x94Cl, compounds of the formula II are obtained in which R30 is R32(R)Nxe2x80x94COxe2x80x94N(R)xe2x80x94R31. Correspondingly, with isothiocyanates and thiocarbamoyl chlorides the analogous thiourea derivatives are obtainable; by reaction of the amino groups with reactive carboxylic acid derivatives, thiocarboxylic acid derivatives, sulfonic acid derivatives, sulfinic acid derivatives and sulfamoyl chlorides, respectively, (thio)acylamines, sulfonylamines, sulfinylamines and sulfamides are obtainable. Like compounds of the formula VII, also compounds can also be prepared and employed into the synthesis in which in the formula VII the group PGxe2x80x94N(R)xe2x80x94 is replaced by a group which is a precursor for an amino group and which is then converted into an amino group in a further reaction step. For example, a compound of the formula VI can first be reacted with a nitro compound of the formula O2Nxe2x80x94R31xe2x80x94LG or a cyano compound of the formula NCxe2x80x94R31xe2x80x94LG to give a compound corresponding to the compound of the formula VII, then the nitro group or the cyano group can be converted into the amino group, for example by catalytic hydrogenation, and then the amino group can be converted into the desired target group, for example using an isocyanate of the formula R32xe2x80x94Nxe2x95x90Cxe2x95x90O to give a urea derivative in which R30 is R32NHxe2x80x94COxe2x80x94NHxe2x80x94R31, or using other compounds. According to this procedure, numerous further compounds of the formula I can be synthesized, the reactions to be carried out always being standard processes which are familiar to the person skilled in the art.
Very generally, the individual steps in the preparation of the compounds of the formula I can be carried out according to or analogously to known methods familiar to the person skilled in the art. Depending on the individual case, it may be appropriate here, as already explained, in all steps in the synthesis of the compounds of the formula I to temporarily block functional groups which could lead to secondary reactions or undesired reactions by a protective group strategy suited to the synthesis problem, which is known to the person skilled in the art.
The explained procedure of not directly introducing functional groups into the molecule in the final form, but first introducing precursors into the molecule and then synthesizing the final functional group at the stage of an intermediate can correspondingly also be used, as already mentioned, for other parts of the molecule of the formula I, for example for the group R1 or the group R3.
Compounds of the formula II in which W is 
and Y is a carbonyl group, can be prepared, for example, by reacting compounds of the formula VIII 
in which R1, A, L, m1 and m2 are defined as indicated above, in a Bucherer reaction as described above for the preparation of the compounds of the formula V, to give compounds of the formula IX 
and converting these using a reagent which introduces the radical xe2x80x94Bxe2x80x94G into the molecule, as described above for the preparation of the compounds of the formula VI, into compounds of the formula X 
where in the compounds of the formulae IX and X the groups R1, A, B, G and L and also m1 and m2 have the meanings indicated above. The compounds of the formula X can then be reacted in turn, correspondingly to the reactions of the compounds of the formula VI described above, with a reagent of the formula R30xe2x80x94LG or a reagent of the formula PGxe2x80x94N(R)xe2x80x94R31xe2x80x94LG.
If W is R1xe2x80x94Axe2x80x94C(R13)xe2x95x90C or the radical 
this structural element can be introduced, for example, by condensing the corresponding aldehyde or the corresponding ketone with a dioxo- or thioxooxoimidazolidine, which contains an unsubstituted methylene group in the position which corresponds to the group W, analogously to known methods.
The amino compounds of the formula III are commercially available or can be synthesized from starting compounds which are commercially available or are obtainable according to or analogously to literature procedures according to or analogously to well known standard processes.
Compounds of the formula I in which W is R1xe2x80x94Axe2x80x94C(R13) can also be obtained as follows:
By reaction of xcex1-amino acids or N-substituted xcex1-amino acids obtainable according to standard processes, or preferably their esters, for example the methyl ester, ethyl ester, tert-butyl ester or benzyl ester, for example of compounds of the formula XI, 
in which R1, R13, R30 and A are defined as indicated above, with an isocyanate or isothiocyanate, for example of the formula XII, 
in which B, E, R, R2, R3, e and h are defined as indicated above and U is isocyanato or isothiocyanato, urea derivatives or thiourea derivatives are obtained, for example of the formula XIII, 
for which the definitions indicated above apply and in which Z is oxygen or sulfur. The compounds of the formula XIII can be cyclized by heating with acid to give compounds of the formula Ia 
for which the meanings indicated above apply. The cyclization of the compounds of the formula XIII to the compounds of the formula Ia can also be carried out by treatment with bases in inert solvents, for example by treatment with sodium hydride in an aprotic solvent such as dimethylformamide. During the cyclization, functional groups can in turn be present in protected form.
Compounds of the formula I in which W is R1xe2x80x94Axe2x80x94C(R13) can also be obtained by reacting a compound of the formula XI with an isocyanate or isothiocyanate of the formula XIV 
in which B and U are defined as indicated above for the formula XII and Q is an alkoxy group, for example a (C1-C4)-alkoxy group such as methoxy, ethoxy or tert-butoxy, a (C6-C14)-aryloxy group, for example phenoxy, or a (C6-C14)-aryl-(C1-C4)-alkoxy group, for example benzyloxy. In this case, a compound of the formula XV 
is obtained, in which Z is oxygen or sulfur and A, B, Q, R1, R13 and R30 are defined as indicated above for the formulae XI and XIV, which is then cyclized under the influence of an acid or of a base, as described above for the cyclization of the compounds of the formula XIII, to a compound of the formula XVI 
in which W is R1xe2x80x94Axe2x80x94C(R13) and Z, B, Q and R30 are defined as indicated above. Starting from the compound of the formula XVI, a compound of the formula Ia can then be obtained, for example, by hydrolysis of the group COxe2x80x94Q to the carboxylic acid COOH and subsequent coupling to a compound of the formula III, as described above for the coupling of the compounds of the formulae II and III. In this synthesis process, too, functional groups can again be present in protected form or in the form of precursors.
A further method for the preparation of compounds of the formula Ia is, for example, the reaction of compounds of the formula XVII, 
in which W is R1xe2x80x94Axe2x80x94C(R13) and for which the definitions indicated above otherwise apply, with phosgene or thiophosgene or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928), 1431-1439).
Compounds of the formula Ia in which Z is oxygen can also be prepared by first coupling a compound of the formula XVIII 
in which R1, R13 and A have the meanings indicated above and PG is an amino protective group such as, for example, a benzyloxycarbonyl group, to a compound of the formula XIX, 
in which B has the meanings indicated above and Qxe2x80x2 is a protected carboxylic acid hydroxyl group, for example an alkoxy group such as tert-butoxy, to give a compound of the formula XX 
in which R1, R13, A, B, PG and Qxe2x80x2 have the meanings indicated above. In the compound of the formula XX, the protective group PG can then be selectively removed from the amino group, for example by hydrogenation in the case of a benzyloxycarbonyl group, and by introduction of a CO group a ring closure can be carried out to give a compound of the formula XXI 
in which R1, R13, A, B and Qxe2x80x2 have the meanings indicated above. For introduction of the carbonyl group, phosgene, for example, or a phosgene equivalent can be used (compare the reaction of the compounds of the formula XVII explained above). An intermediate which can occur or which can specifically be prepared in the conversion of the compound of the formula XX into that of the formula XXI is, for example, an isocyanate. The conversion of the compound of the formula XX into that of the formula XXI can be carried out in one or more steps. For example, the cyclization can be carried out separately in the presence of a base such as sodium hydride after introduction of the carbonyl group, like the cyclizations described above. Compounds of the formula XX in which PG is a benzyloxycarbonyl group can also be converted directly into compounds of the formula XXI without a buidling block such as phosgene being employed for the introduction of the carbonyl group. If compounds of the formula XX in which PG is benzyloxycarbonyl are treated with a base such as sodium hydride, the compounds of the formula XXI can be obtained directly.
In the compounds of the formula XXI, the radical R30xe2x80x94 or the radical PGxe2x80x94NRxe2x80x94R31xe2x80x94 can then be introduced onto the NH group as explained above for the compounds of the formula VI and, after cleavage of the protective group COxe2x80x94Qxe2x80x2 to the carboxylic acid group COOH as described above for the compounds of the formulae VII and II, the desired compound of the formula Ia (where Z=oxygen) can be synthesized. In this synthesis process, too, functional groups can again be present in protected form or in the form of precursors.
A guanidino group contained in the radical R1 can be obtained, for example, from an amino group, which is in turn obtainable, for example, from a nitro group or a cyano group by reduction, using the following reagents:
1. O-Methylisourea (S. Weiss and H. Krommer, Chemiker-Zeitung 98 (1974), 617-618)
2. S-Methylisothiourea (R. F. Borne, M. L Forrester and I. W. Waters, J. Med. Chem. 20 (1977), 771-776)
3. Nitro-S-methylisothiourea (L. S. Hafner and R. E Evans, J. Org. Chem. 24(1959) 57)
4. Formamidinosulfonic acid (K. Kim, Y.-T. Lin and H. S. Mosher, Tetrah. Lett 29 (1988), 3183-3186)
5. 3,5-Dimethyl-1-pyrazolylformamidinium nitrate (F. L. Scott, D. G. O""Donovan and J. Reilly, J. Amer. Chem. Soc. 75(1953), 4053-4054)
6. N,Nxe2x80x2-Di-tert-butyloxycarbonyl-S-methylisothiourea (R. J. Bergeron and J. S. McManis, J. Org. Chem. 52 (1987), 1700-1703)
7. N-Alkoxycarbonyl-, N,Nxe2x80x2-dialkoxycarbonyl-, N-alkylcarbonyl- and N,Nxe2x80x2-dialkylcarbonyl-S-methylisothiourea (H. Wollweber, H. Kxc3x6lling, E. Niemers, A. Widdig, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim. Forsch./Drug Res. 34 (1984), 531-542).
Amidines can be prepared from the corresponding cyano compounds by addition of alcohols, for example methanol or ethanol, in acidic anhydrous medium, for example dioxane, methanol or ethanol, and subsequent aminolysis, for example treatment with ammonia in alcohols such as, for example, isopropanol, methanol or ethanol (G. Wagner, P. Richter and Ch. Garbe, Pharmazie 29 (1974), 12-55). A further method of preparing amidines is the addition of hydrogen sulfide to the cyano group, followed by a methylation of the resulting thioamide and subsequent reaction with ammonia (GDR Patent No. 235 866). Hydroxylamine can furthermore be added to the cyano group, N-hydroxyamidines being formed which, if desired, can likewise be converted into the amidines, for example by hydrogenation.
With respect to the preparation of the compounds of the formula I, the contents of WO-A-95/14008, EP-A-796 855 and the applications corresponding to it, as well as of WO-A-96/33976 are incorporated herein by reference in their entirety. For example, with respect to the preparation of the compounds of the formulae V and VI in racemic form and in enantiomerically pure form, reference is made to the corresponding details in WO-A-96/33976, which is also incorporated by reference in its entirety.
The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, allergic disorders or asthma. The compounds of the formula I and their physiologically tolerable salts and derivatives can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy or prophylaxis. They can be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral administration and which as active constituent contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and derivatives in addition to customary pharmaceutically innocuous excipients and/or additives.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and derivatives for use as pharmaceuticals, the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives for the production of pharmaceuticals for the therapy and prophylaxis of the diseases described above or below, for example for the therapy and prophylaxis of inflammatory disorders, and the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and derivatives and a pharmaceutically innocuous carrier, i.e., customary pharmaceutically innocuous excipients and/or additives.
The pharmaceuticals can be administered systemically or locally. They can be administered, for example, in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, powders, solutions, syrups, emulsions, suspensions or in other pharmaceutical forms. However, administration can also be carried out vaginally or rectally, for example in the form of suppositories, or parenterally or by implantation, for example in the form of injection solutions or infusion solutions, microcapsules or rods, or topically or percutaneously, for example in the form of ointments, solutions or tinctures, or in another way, for example in the form of nasal sprays or aerosol mixtures. If solutions are parenterally administered they can be aministered, for example, intravenously, intramuscularly, subcutaneously, intraarticularly, intrasynovially or in another manner.
The pharmaceutical preparations according to the invention can be prepared in a manner known per se, it being possible to use pharmaceutically inert inorganic and/or organic excipients in addition to the compound(s) of the formula I and/or its/their physiologically tolerable salts and derivatives. For the preparation of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, polyethylene glycols, natural or hardened oils etc. Suitable excipients for the preparation of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, diols, polyols, sucrose, invert sugar, glucose, vegetable oils etc. Suitable excipients for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and derivatives.
In addition to the active compounds and excipients, the pharmaceutical preparations can additionally contain auxiliaries or additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, solvents or solubilizers, means for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and derivatives. Furthermore, they can also contain one or more other therapeutically or prophylactically active substances in addition to at least one compound of the formula I and/or its physiologically tolerable salts and derivatives, for example substances having antiinflammatory action. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 100 mg, of active compound of the formula I and/or its physiologically tolerable salts and derivatives per dose.
If the compounds of the formula I or pharmaceutical preparations containing them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be effected, for example, using a spray, an atomizer, a pump atomizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the formula I as an aerosol can be prepared by the process well known to the person skilled in the art For their preparation, for example, solutions or dispersions of the compounds of the formula I in water, water-alcohol mixtures or suitable saline solutions using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example chlorofluorohydrocarbons and/or fluorohydrocarbons are suitable.
The compounds of the formula I have the ability to inhibit cell-cell interaction processes and cell-matrix interaction processes in which interactions between VLA-4 with its ligands play a part The efficacy of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which contain the VLA-4 receptor, for example of leucocytes, to ligands of this receptor is measured, for example to VCAM-1, which for this purpose can advantageously also be prepared by genetic engineering. Details of such an assay are described further below. In particular, the compounds of the formula I are able to inhibit the adhesion and the migration of leucocytes, for example the adhesion of leucocytes to endothelial cells whichxe2x80x94as explained abovexe2x80x94is controlled via the VCAM-1/VLA-4 adhesion mechanism. Besides as antiinflammatory agents, the compounds of the formula I and their physiologically tolerable salts and derivatives are therefore generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between the VLA-4 receptor and its ligands or can be affected by an inhibition of this interaction, and in particular they are suitable for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of leucocyte adhesion and/or leucocyte migration or are associated therewith, and for whose prevention, alleviation or cure the adhesion and/or migration of leucocytes should be decreased.
The present invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts and derivatives for the inhibition of the adhesion and/or migration of leucocytes or for the inhibition of the VLA-4 receptor and the use of the compounds of the formula I for the production of pharmaceuticals for this purpose, i.e., of pharmaceuticals for the therapy or prophylaxis of diseases in which leucocyte adhesion and/or leucocyte migration exhibits an undesired extent, or for the therapy or prophylaxis of diseases in which VLA-4dependent adhesion processes play a part, and also the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of diseases of this type.
The compounds of the formula I can be employed as antiinflammatories in the case of inflammatory symptoms of very different cause in order to prevent, to decrease or to suppress the undesired or harmful consequences of inflammation. They are used, for example, for the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus, for the therapy or prophylaxis of inflammatory disorders of the central nervous system such as, for example, multiple sclerosis, or for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). They are furthermore suitable for the therapy or prophylaxis of cardiovascular disorders, arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or formation of tumor metastases in various malignancies, of malaria as well as of other diseases in which blocking of the integrin VLA-4 and/or influencing of the leucocyte activity appears appropriate for prevention, alleviation or cure.
The dose when using the compounds of the formula I can vary within wide limits, and as customary it is to be tailored to the individual conditions in each individual case, as is known to the physician. It depends, for example, on the nature and severity of the disease to be treated, on the compound employed or whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the formula I. In general, in the case of oral administration, a daily dose of approximately 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, in particular 0.3 to 2 mg/kg (in each case per kg of body weight) is appropriate in an adult to achieve effective results. In the case of intravenous administration, the daily dose is in general approximately 0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg of body weight. In particular when relatively large amounts are administered, the daily dose can be divided into a number, for example 2, 3 or 4, of part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.
Apart from as pharmaceutical active compounds in human medicine and veterinary medicine, the compounds of the formula I and their salts and derivatives which are suitable for the use concerned, can furthermore be employed for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples, and as auxiliaries or as a scientific tool in biochemical investigations in which VLA-4 blockage or an effect on cell-cell or cell-matrix interactions is intended. Furthermore, the compounds of the formula I and their salts can be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds which are obtainable from compounds of the formula I, for example, by modification or introduction of radicals or functional groups, for example by esterification, reduction, oxidation or other conversions of functional groups.